Chest
Volume 114, Issue 5, Supplement, November 1998, Pages 445S-469S
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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 post-translational carboxylation of glutamate residues to γ-carboxyglutamates (Gla) on the N-terminal regions of vitamin K-dependent proteins.3, 4, 5, 6, 7, 8 The process of γ-carboxylation permits the coagulation proteins to undergo a conformational change9, 10, 11 in the presence of calcium ions, a necessary

Effects of Warfarin on Bone Metabolism

Gla proteins synthesized in bone include osteocalcin, protein S, and matrix Gla protein.16, 17, 18 Warfarin interferes with the carboxylation of these proteins and inhibits the effect of vitamin K in osteoblasts.19 These effects of warfarin could be responsible for bone abnormalities that can occur in neonates from women treated with warfarin during pregnancy.20,21 However, there is no evidence that warfarin has adverse effects on bone metabolism when administered to children or adults.

Pharmacokinetics and Pharmacodynamics of Warfarin

Warfarin (a 4-hydroxy compound) is the most widely used oral anticoagulant in North America. It has a predictable onset and duration of action and excellent bioavailability.22,23 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 GI tract and reaches maximal blood

Monitoring Oral Anticoagulant Therapy

The PT test is the most common method used for monitoring oral anticoagulant therapy.67 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 citrated plasma. The term “thromboplastin” traditionally refers to a phospholipid-protein extract of tissue, usually lung, brain, or

The Antithrombotic Effect of Warfarin

The conventional view is that the 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, is more important than reduction of factors VII and IX for the antithrombotic effect of warfarin. The evidence supporting this hypothesis is not definitive and comes

Standardization of the Prothrombin Time

The history of standardization of the PT has been reviewed by Poller69 and by Kirkwood.80 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 > 20 years until 1985. In 1977, the World Health Organization (WHO) designated a batch of human brain thromboplastin as the first international reference preparation (IRP) for thromboplastin.69,80 The first IRP was later replaced by a new

The Lack of Reliability of the INR System When Used at the Onset of Warfarin Therapy and for Screening for a Coagulopathy in Patients With Liver Disease

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,84,85 particularly to factors VII and X. Since these three vitamin K-dependent clotting factors have varying rates of plasma clearance, their relative contributions to the prolongation of the PT are different during the induction phase of warfarin therapy (first few

Practical Dosing

Following administration of warfarin, an observable anticoagulant effect is delayed until newly synthesized dysfunctional vitamin K-dependent clotting factors replace the normal clotting factors as the latter are cleared from the circulation. Depending on the dose administered, the delay may range from 2 to 7 days. If a rapid anticoagulant effect is required, an initial dose of heparin should be used and overlapped with warfarin for at least 4 days. Although it has been common practice to

Improving Anticoagulant Control

The effectiveness and safety of warfarin are critically dependent on maintaining the INR in the therapeutic range. Therefore, every effort should be made to maintain the patient in the designated therapeutic range. This objective is facilitated by always aiming for an INR level that is in the mid-level of the INR range (ie, 2.5 for a designated range of 2.0 to 3.0 and 3.0 for a designated range of 2.5 to 3.5). The impact of maintaining good anticoagulant control was highlighted by reanalysis of

Anticoagulation Management Services

In North America, oral anticoagulation therapy is usually managed by a patient's personal physician (routine medical care [RMC]).124 An alternative approach is the use of anticoagulation management services (AMS) or anticoagulation clinics,125 in which the management is conducted by registered nurses, nurse practitioners, pharmacists, or physician assistants using dosage-adjustment protocols developed by experts in the field. The latter approach has the advantage of better coordination by

Clinical Outcomes: RMC vs AMS

Table 5 summarizes the four studies in which investigators used clinical outcomes to compare two models of care in a single setting.126, 127, 128, 129 All of these studies used a before and after design and none were prospective randomized trials. In two studies,126,127 the same patient groups were observed first in an RMC setting and then in an AMS setting. The third study128 involved two defined cohorts of patients128 and the fourth report129 provided data on three sequential inception

Cost-Effectiveness of RMC vs AMS

Attempts have been made to compare the relative costs of the two approaches. Gray et al143 estimated a savings of $860 per patient-year of therapy (in 1985 dollars) due to reduced hospital days in his study of patients treated by an AMS vs RMC. Chiquette et al129 found a savings of $1,650 per patient-year of therapy in their comparative study due to a significant reduction in hospitalizations and emergency department visits. The fact that neither of the two studies was properly randomized means

Point-of-Care Patient Self-Testing and Patient Self-Management

Recent technological advances in point-of-care PT measurement offer the potential for both simplifying and improving oral anticoagulation management. Three classes of portable PT monitors, suitable for patient self-testing at home, are currently available for point-of-care diagnostic testing144 (Table 6). Each of these monitors measures the thromboplastin-mediated clotting time that is then converted to a plasma PT equivalent by a microprocessor and expressed as a PT or INR.

The validity of this

Patient Self-Testing

Anderson et al158 confirmed the feasibility and assessed the accuracy of patient self-testing at home in a group of 40 individuals who monitored their own therapy over a period of 6 to 24 months. Based on either narrow or expanded target therapeutic ranges, they observed a mean level of agreement per patient with reference plasma PTs of 83% by narrow criteria and 96% by expanded criteria. Ninety-seven percent of the patients preferred home testing to standard management.

White et al,159 in a

Patient Self-Management

In 1974, Erdman et al161 first tested the concept of patient self-management of oral anticoagulation based on physician-derived guidelines with PTs obtained on plasma samples by routine laboratory instrumentation. In nearly 200 patients with prosthetic heart valves managing their own therapy, they claimed a greater degree of satisfactory anticoagulation (98% of 195 patients enrolled) compared with a retrospective survey of standard management patients who achieved only a 71% degree of adequate

Summary and Conclusions

Based on a number of observational studies, patients treated by an AMS achieve better therapeutic outcomes than those treated under a model of RMC. This difference may be due to maintaining better therapeutic control in the AMS, but it could be due to bias. Better-quality studies are needed to confirm these differences.

Newer models of warfarin management are emerging based on point-of-care PT testing, allowing patients to determine their own PT and adjust their own warfarin dose. Initial

Computerized Systems for Predicting Warfarin Dosage

A number of computerized programs have been developed to assist physicians and other health-care providers with oral anticoagulant dosing.166, 167, 168, 169 In a recent randomized trial, the reliability of three established computerized dosage programs was compared with warfarin dosing by experienced medical staff in patients who attended the same established outpatient clinic.170 All three programs gave satisfactory control compared with empiric dosage adjustment by experienced physicians in

Management of Patients with High INR Values with or without Bleeding

If a patient has an elevated INR and is not bleeding or does not require surgery, then it is reasonable to reduce the INR to a safer level of < 5.0 either by omitting a dose of warfarin or by administering vitamin K1. If the patient has serious bleeding, the INR should be reduced to 1.0 as soon as possible. If the patient requires elective or urgent surgery, it is reasonable to reduce the INR to 1.0 to 1.5 at the time of surgery.

Three approaches can be used to reduce the INR. The first and

Discontinuation of Warfarin Therapy

White and associates159 reported that it takes about 4 days for the INR to return to the normal range when warfarin therapy is stopped in patients whose INR is between 2.0 and 3.0.

Vitamin K1

Ideally, vitamin K1 should be administered in a dosage that rapidly reduces the INR into a safe range without (1) overshooting the lower limit of the targeted range, (2) rendering the patient resistant to warfarin when therapy with it is restarted, and (3) exposing the patient to a risk of an anaphylactoid reaction. There is a strong relationship between the level of the INR and the risk of bleeding. The risk of bleeding rises sharply when the INR exceeds 5.0, but bleeding is increased,

Management of the Patient Receiving Long-Term Warfarin Therapy who Requires Surgery

This subject has been reviewed recently.181 Several approaches can be used to manage patients who are being treated with warfarin for an underlying thrombotic disorder and require surgery. The choice depends on personal preferences and the risk of thrombosis. With each of the following options, the length of time for warfarin dosage reduction and for heparin or low-molecular-weight heparin (LMWH) use preoperatively can be shortened by administering vitamin K1 24 to 48 h before surgery to

Management of the Patient who Bleeds During Warfarin Therapy

The short-term management of patients who bleed with an excessively prolonged INR has been discussed above. The long-term management 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. There are two general principles that should be followed: (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 moderate intensity 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 7) (see below).

Oral

Prevention of Venous Thromboembolism

Oral anticoagulants are effective in preventing venous thrombosis after hip surgery185, 186, 187 and major gynecologic surgery188,189 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,185,186 the evening before surgery, or on the first postoperative day.187 The risk of clinically important bleeding with the moderate-intensity regimen is small, but because warfarin prophylaxis is more complicated to use than fixed

Treatment of Deep Vein Thrombosis

The optimal duration of oral anticoagulant therapy has been reviewed by Hirsh.199 The duration of treatment is influenced by the following factors: (1) idiopathic vs secondary thrombosis with a reversible cause—a longer course of therapy should be used if the thrombosis is idiopathic; (2) proximal vs calf vein thrombosis—a longer course of therapy is indicated in patients with proximal vein thrombosis; (3) first episode vs recurrent thrombosis—a longer course of treatment is indicated in

Primary Prevention of Myocardial Ischemia

The Thrombosis Prevention Trial2 evaluated low-intensity warfarin therapy and low-dose aspirin therapy in 5,499 men between the ages of 45 and 69 years at high risk of ischemic heart disease. The primary outcome was the prevention of acute ischemic coronary events defined as the composite of coronary death and fatal and nonfatal myocardial infarction. The targeted INR was 1.3 to 1.8 and the mean warfarin dose was 4.1 mg/d.

The annual incidence of acute ischemic coronary events was 1.4% per year

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 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 from

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 SPAF trial,225 the Boston Area Anticoagulation Trial for Atrial Fibrillation,226 the Stroke Prevention in Atrial Fibrillation Trial;227 one trial was carried out in Denmark, the Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation study (AFASAK);228 and the other was performed in Canada, the Canadian Atrial Fibrillation Anticoagulation study.229 In two of the trials

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. Thus, oral anticoagulants have not been compared with an untreated control group or with another antithrombotic regimen in patients with valvular heart disease (with or without atrial fibrillation) or in patients who have suffered at least one episode of systemic embolism. Long-term oral

Adverse Effects

Bleeding is the main complication of oral anticoagulant therapy. The risk of bleeding is influenced by the intensity of anticoagulant therapy130,206,221, 222, 223,238 (Table 7), by the patient's underlying clinical disorder,130,239 and by the concomitant use of aspirin, which both impairs platelet function and produces gastric erosions, and when used in very high doses, it impairs synthesis of vitamin K-dependent clotting factors.54,59

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.21 This complication is discussed in detail in the chapter on “Use of Antithrombotic Agents During Pregnancy,” page 524S. 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

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