| | Coumarin therapy in thrombosis
Oral anticoagulants are the most commonly used agents in the long-term prophylaxis and treatment of arterial and venous thrombotic disorders. As new and expanded indications for their use, such as the prevention of recurrent myocardial infarction or the treatment of systemic embolism in atrial fibrillation, are developed, the use of oral anticoagulants is rising. Also, in North America, oral anticoagulants are used commonly for preventing venous thromboembolism following orthopedic surgery. This article reviews the pharmacology of warfarin sodium, the most commonly used oral anticoagulant in North America, and discusses practical aspects of the use of this agent in thrombotic disorder management.
Pharmacology  The vitamin K cycle Vitamin K is responsible for the posttranslational conversion of glutamate residues into Gla in a limited number of proteins, the best known of which are the blood coagulation factors II, VII, IX, X, protein C, protein S, and protein Z, and bone matrix proteins. The best-known bone matrix proteins are osteocalcin and matrix Gla-protein (MGP) [1]. γ-carboxyglutamic acid permits the binding of calcium by these proteins, and in the presence of calcium, the coagulation factors undergo a conformational change required for their binding to various active cofactors on cell surfaces [2]. The reduced form of vitamin K (KH2) acts as a coenzyme for carboxylase. The oxidation of vitamin KH2 by oxygen into vitamin K epoxide (KO) provides energy to fix carbon dioxide (CO2) at the γ-position of a glutamate residue. The vitamin KO then is recycled, first by vitamin KO reductase to vitamin K (quinone) and then by vitamin K reductase to vitamin KH2 (hydroquinone). It is essential that each molecule of vitamin K is recycled several hundred times before being metabolized. The oral anticoagulants inhibit vitamin KO reductase and possibly vitamin K reductase, thereby depleting vitamin KH2 and causing the build-up of vitamin KO in the tissues such as the liver and plasma. The most important forms of vitamin K are phylloquinones (vitamin K1) and menaquinones (vitamin K2) [1]. Phylloquinones are found in green, leafy vegetables such as spinach, cabbage, and broccoli. Deficiencies of these vegetables in the diet can cause vitamin K deficiency, whereas excessive amounts can reverse the effects of oral anticoagulants. The menaquinones occur in various foods such as yogurt and organ meats. They also are produced by the bacterial flora of the colon and possibly the small intestine. Factors interfering with the production or absorption of these menaquinones, such as. broad-spectrum antibiotics, may lead to vitamin K deficiency [3] and interference with anticoagulant control. Also, certain cephalosporins containing an N-methyl-thiotetrazole side chain may interfere directly with vitamin KO reductase in the liver [4], thereby leading to vitamin K deficiency. Most of the vitamin K stores in the liver are menaquinones, and it is thought that most of these originate from the diet rather than intestinal flora [1]. Large doses of vitamin K can overcome the blockade of vitamin KH2 by oral anticoagulants, presumably because vitamin K reductase is less sensitive to the coumarins than is vitamin KO reductase [1]. This reversal of oral anticoagulants applies to first-generation agents such as warfarin but not to second-generation rodenticides known as the “super warfarins,” which have an extremely long half-life. Accidental consumption of these agents requires repeated injections of vitamin K and fresh-frozen plasma for up to 1 or 2 years to completely overcome their effects [5], [6]. Pharmacokinetics and pharmacodynamics of warfarin There are two distinct chemical groups of oral anticoagulants: the 4-hydroxy coumarin derivatives (eg, warfarin sodium) and the indane-1, 3-dione derivatives (eg, phenindione) [7]. The coumarin derivatives are the oral anticoagulants of choice, because they are associated with fewer nonhemorrhagic side effects than are the indanedione derivatives. In North America, the most commonly used agent is coumarin (Coumadin, Bristol-Myers Squibb, Princeton, NJ), but in recent years various generic forms of warfarin sodium have been introduced. Warfarin is a racemic mixture of stereo isomers (R & S forms). Warfarin is highly water-soluble and is highly bioavailable [8]. Peak absorption occurs around 90 minutes, and the half-life is between 36 and 42 hours. Warfarin is highly protein-bound (primarily albumen), and only the nonprotein-bound material is biologically active. Any drug or chemical that also is bound to albumen may displace warfarin from its protein-binding sites and thereby increase the biologically active material [8]. Warfarin is metabolized in the liver by the p450 (CYP2C9) system of enzymes. Interference with the CYP2C9 enzymes by various drugs or a mutation in the gene coding for one of the common CYP2C9 enzymes can interfere markedly with the metabolism of warfarin [9]. The anticoagulant effect of warfarin is mediated by the inhibition of the vitamin K-dependent gamma-carboxylation of coagulation factors II, VII, IX, and X [7], [8]. This results in the synthesis of immunologically detectable but biologically inactive forms of these coagulation proteins. Warfarin also inhibits the vitamin K-dependent gamma-carboxylation of proteins C, S [9], and Z [10]. Protein C circulates as a proenzyme that is activated on endothelial cells by the thrombin/thrombomodulin complex to form activated protein C. Activated protein C in the presence of protein S inhibits activated factor VIII and V activity [11]. Therefore, vitamin K antagonists such as warfarin create a biochemical paradox by producing an anticoagulant effect because of the inhibition of procoagulants (factors II, VII, IX, and X) and a potentially thrombogenic effect by impairing the synthesis of naturally occurring inhibitors of coagulation (proteins C and S) [11]. Heparin or low–molecular-weight heparin and warfarin treatment should overlap by 4 to 5 days when warfarin treatment is started in patients with thrombotic disease. The role of protein z in the coagulation process is less definite. The anticoagulant effect of warfarin is delayed until the normal clotting factors are cleared from the circulation, and the peak effect does not occur until 36 to 72 hours after drug administration [12]. During the first few days of warfarin therapy, the prothrombin time (PT) reflects mainly the depression of factor VII, which has a half-life of 5 to 7 hours. Equilibrium levels of factors II, IX, and X are not reached until about 1 week after therapy starts. The use of small initial daily doses (eg, 5 mg) is the preferred approach for initiating warfarin treatment [13]. The dose-response relationship to warfarin therapy varies widely between individuals; therefore, the dose must be monitored carefully to prevent overdosing or underdosing. A number of factors influence the anticoagulant response of warfarin in individual patients. These include inaccuracies in laboratory testing and noncompliance of patients but more importantly reflect the influence of dietary changes or the influence of drugs that interfere with the metabolism of warfarin. The availability of vitamin K can be influenced by dramatic changes in dietary intake or by drugs such as antibiotics, which interfere with the synthesis of vitamin K in the gastrointestinal tract. Many drugs may interact with warfarin; however, a critical appraisal of the literature reporting such interactions indicates that the evidence substantiating many of the claims is limited [14]. The interactions of drugs and food with warfarin are reviewed in detail in a recent publication [8]. Aspirin is particularly problematic, because it interferes with platelet function and displaces warfarin from its protein binding, thus augmenting its biological activities. As with nonsteroidal anti-inflammatory drugs (NSAIDs) it may cause gastric erosions, thus creating a site for bleeding. Nonetheless, in certain patients, the use of aspirin and warfarin is indicated to improve efficacy, even though bleeding may be increased somewhat. It is important that patients be warned against taking any new drugs without the knowledge of their attending physician, and it is prudent to monitor the International Normalized Ratio (INR) more frequently when any drug (including natural compounds) is added or withdrawn from the regimen of patients treated with an oral anticoagulant. Laboratory monitoring and therapeutic range The laboratory test most commonly used to measure the effects of warfarin is the one–stage PT test. The PT test is sensitive to reduced activity of factors II, VII, and X but insensitive to reduced activity of factor IX. There has been confusion about the appropriate therapeutic range, because the different tissue thromboplastins used for measuring the PT vary considerably in sensitivity to the vitamin K-dependent clotting factors and in response to warfarin [15], [16]. In order to promote standardization of the PT test for monitoring oral anticoagulant therapy, the World Health Organization (WHO) developed an international reference thromboplastin from human brain tissue and recommended that the PT ratio be expressed as the INR [8]. The INR is the PT ratio obtained by testing a given sample using the WHO reference thromboplastin. For practical clinical purposes, the INR for a given plasma sample is equivalent to the PT ratio obtained using a standardized human brain thromboplastin known as the Manchester Comparative Reagent, which has been used widely in the United Kingdom [8]. In recent years, thromboplastins with a high sensitivity have been used commonly. In fact, many centers have been using the recombinant tissue factor, which has an ISI value 0.9 to 1.0, giving an INR equivalent to the PT ratio. Warfarin is administered in an initial dose of 5 mg per day for the first 2 days, and the daily dose is then adjusted according to the INR. Heparin or low-molecular–weight heparin therapy is discontinued on the 5th day following initiation of warfarin therapy, provided the INR is prolonged into the recommended therapeutic range (INR 2.0 to 3.0) for at least 2 consecutive days [8]. Frequent INR determinations are required initially to establish therapeutic anticoagulation. Once the anticoagulant effect and patient's warfarin dose requirements are stable, the INR should be monitored every 1 to 3 weeks throughout the course of warfarin therapy. If there are factors that may produce an unpredictable response to warfarin (eg, concomitant drug therapy) [8], [13], however, the INR should be monitored more frequently to minimize the risk of complications caused by poor anticoagulant control. Adverse effects of oral anticoagulants Bleeding The major adverse effect of oral anticoagulant therapy is bleeding [17]. A number of risk factors have been identified that predispose to bleeding on oral anticoagulants [18], [19], [20], [21]. The most important factor influencing bleeding risk is the intensity of the INR. [18], [19], [20], [21], [22] Other factors include a history of bleeding, previous history of stroke or myocardial infarction, hypertension, renal failure, diabetes, and a decreased hematocrit [19]. Researchers have attempted to quantitate the bleeding risk according to these underlying clinical factors [19]. Introduction of a multi-component intervention combining patient education and alternative approaches to the maintenance of the INR resulted in a reduced frequency of major bleeding in the patients in this group [20]. Furthermore, patients in the intervention group were within the therapeutic INR a significantly greater amount of time than were patients in the standard care group [20]. In a retrospective cohort study of patients with an INR greater than 6.0, it was shown that a prolonged delay to the return of the INR to the therapeutic range was seen in patients who had an INR over 4.0 after two doses of warfarin were withheld, patients with an extreme elevation of the INR [21], and in older patients, particularly those with decompensated congestive heart failure and active cancer. Numerous randomized clinical trials have demonstrated that clinically important bleeding is lower when the targeted INR is 2.0 to 3.0 and that bleeding increases exponentially when the INR increases above 4.5 or 5.0 [16], [22], [23]. There is a strong relationship between the percentage of time that patients are within the targeted INR and bleeding and recurrent thrombosis. Oral anticoagulant therapy in elderly patients presents further problems [24], [25]. Many of these patients require long-term anticoagulants because of their underlying clinical conditions, which increase with age, while at the same time they are more likely to have underlying causes for bleeding including the development of cancer, intestinal polyps, renal failure, and stroke. In addition, they are more prone to having frequent falls. The daily requirements for warfarin to maintain the therapeutic INR also decreases with age, presumably because of decreased clearance of the drug [26]. Therefore, before initiating oral anticoagulant treatment in elderly patients the risk/benefit ratio of treatment must be considered. If these patients are placed on oral anticoagulant therapy, careful attention to the INR is required. Patients with cancer are more likely to bleed on oral anticoagulant treatment [27]. Compared with patients on oral anticoagulants who do not have cancer, patients with cancer have a higher incidence of major and minor bleeding, and anticoagulant withdrawal is more frequently caused by bleeding. Patients with cancer have a higher thrombotic complication rate and a higher bleeding rate regardless of the INR, whereas bleeding in noncancer patients was seen only when the INR was greater than 4.5. Safer and more effective anticoagulant therapies are required for the treatment of venous thromboembolism in patients with cancer [27]. Management of overanticoagulation The approach to the patient with an elevated INR depends on the degree of elevation of the INR and the clinical circumstances [13]. Options include temporary discontinuation of warfarin treatment, administration of vitamin K, or administration of blood products such as fresh frozen plasma or prothrombin concentrate to replace the vitamin K–dependant clotting factors. If the increase is mild, and the patient is not bleeding, no specific treatment is necessary other than reduction in the warfarin dose. The INR can be expected to decrease during the next 24 hours with this approach. With more marked increase of the INR in patients who are not bleeding, treatment with small doses of vitamin K1 (eg, 1 mg), given orally or by subcutaneous injection, could be considered. With very marked increase of the INR, particularly in a patient who is actively bleeding or at risk for bleeding, the coagulation defect should be corrected. Vitamin K can be given by the intravenous or subcutaneous route or by the oral route [13]. Where possible, the oral route is preferred. If ongoing anticoagulation with warfarin is planned, then repeated small doses of vitamin K should be given, so that there is no problem with warfarin resistance [28], [29]. Reported side effects of vitamin K include flushing, dizziness, tachycardia, hypotension, dyspnea, and sweating [30]. Intravenous administration of vitamin K1 should be performed with caution to avoid inducing an anaphylactoid reaction. The risk of anaphylactoid reaction can be reduced by slow administration of vitamin K1. In most patients, intravenous administration of vitamin K1 produces a demonstrable effect on the INR within 6 to 8 hours and corrects the increased INR within 12 to 24 hours. Because the half-life of vitamin K1 is less than that of warfarin sodium, a repeat course of vitamin K1 may be necessary. If bleeding is very severe and life threatening, vitamin K therapy can be supplemented with concentrates of factors II, VII, IX, and X. When bleeding occurs in a patient on oral anticoagulants, it is important to consider the site of bleeding. Bleeding from the upper gastrointestinal tract is seen commonly in patients on oral anticoagulants, and the concommitant use of other medications is often an association [31]. When the bleeding is controlled, it is important to conduct the necessary investigations to identify bleeding lesions in the gastrointestinal or genitourinary tract, which are often unsuspected [13]. Nonhemorrhagic adverse effects Coumarin-induced skin necrosis is a rare but serious complication that requires immediate cessation of oral anticoagulant therapy [32], [33]. It usually occurs between 3 and 10 days after therapy has commenced. It is more common in women and most often involves areas of abundant subcutaneous tissues, such as the abdomen, buttocks, thighs, and breast. The mechanism of coumarin-induced skin necrosis, which is associated with microvascular thrombosis, is uncertain but appears to be related, at least in some patients, to depression of protein C level. Patients with congenital deficiencies of protein C may be particularly prone to developing coumarin skin necrosis. Oral anticoagulants and pregnancy Oral anticoagulants cross the placenta and may cause fetal malformations when used during pregnancy [34], [35], [36]. Two specific fetopathic syndromes are associated with oral anticoagulant administration during pregnancy. Treatment with oral anticoagulants during the 6th to 12th weeks of gestation may induce warfarin embryopathy in the fetus. This syndrome consists of skeletal abnormalities ranging from stippled epiphyses to frank skeletal hypoplasia. Although most of reported cases have occurred in infants of mothers receiving warfarin, this syndrome also has been reported to result from phenindanedione or acenocoumarin administration. Spontaneous bleeding and fetal abnormalities more common with doses of warfarin greater than 5 mg per day. Oral anticoagulant administration during the second or third trimester of pregnancy may result in central nervous system abnormalities in the fetus, including abnormalities of the ventricular system (Dandy-Walker malformation), dorsal midline dysplasia, and optic atrophy. Therefore, the use of oral anticoagulants is contraindicated at any time during pregnancy, and they should not be used in women planning a pregnancy. Adjusted-dose heparin or low-molecular–weight heparin can be given safely throughout pregnancy in patients with venous thromboembolism, and from that observation, indications have been extrapolated to include patients requiring anticoagulation to prevent systemic embolism from prosthetic heart valves [35]. Managing patients on long-term oral anticoagulants requiring surgical intervention Physicians commonly are confronted with the problem of managing oral anticoagulants in individuals who require temporary interruption of treatment for surgery or other invasive procedures [37], [38]. In the absence of data from randomized clinical trials, recommendations can only be made based on cohort studies, retrospective reviews, and expert opinions. The most common conditions requiring long-term anticoagulant therapy are atrial fibrillation, mechanical or prosthetic heart valve replacement, and venous thromboembolism [39]. For each of these conditions, the risk of arterial or venous thromboembolism, when anticoagulants have been discontinued, must be weighed against the risk of bleeding if intravenous heparin is applied before or after the surgical procedure, or if oral anticoagulant therapy is continued at the therapeutic level. The possible choices based on the risk/benefit assessment in the individual patient based on a previous American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy include [40]:
1.Discontinuing warfarin for 3 to 5 days before the procedure to allow the INR to return to normal and then restarting therapy shortly after surgery.
2.Lowering the warfarin dose to maintain an INR in the lower or subtherapeutic range during the surgical procedure.
3.Discontinuing warfarin and treating the patient in-hospital with intravenous heparin before and after the surgical procedure until warfarin therapy can be reinstituted. Low–molecular-weight heparin is being used in some of these circumstances.
In a recent review that attempted to estimate the risk versus benefit for the temporary discontinuation of oral anticoagulants and the temporary use of heparin in patients with different conditions requiring oral anticoagulation, further revised recommendations were made [39]. Low–molecular-weight heparin, which can be given by once or twice daily subcutaneous injection, offers a convenient alternative to intravenous unfractionated heparin for patients requiring temporary interruption of warfarin therapy for invasive procedures. Although no randomized clinical trials have been conducted, in a large cohort study, patients with mechanical heart valves, atrial fibrillation, or venous thromboembolism who required an interruption of anticoagulant therapy for various surgical procedures were placed on low–molecular-weight heparin in therapeutic doses after warfarin had been discontinued for 4 to 5 days [41]. The low–molecular-weight heparin was discontinued 12 hours before the procedure and recommenced within 8 to 12 hours after surgery, at which time warfarin was restarted. With this protocol patients were off warfarin for an average of 6 days and they received low–molecular-weight heparin an average of 10.2 days. In 515 patients, major bleeding was seen in only 2, and there were no thromboembolic complications. Two other small studies have shown that low–molecular-weight heparin in therapeutic doses was effective and safe in a similar setting and indicate that low–molecular-weight heparin provides a convenient and less costly alternative to intravenous unfractionated heparin for the temporary interruption of anticoagulant therapy [42], [43]. Alternative approaches to the management of oral anticoagulant therapy Anticoagulant management clinics In recent years, a large number of anticoagulation management clinics have been developed, initially in Europe, and more recently in North America. As described by Ansell et al [44], [45], [46], these anticoagulation management clinics provide coordinated services for patients requiring long-term anticoagulation therapy. Although there have been no randomized clinical trials comparing routine medical care with care given in anticoagulant management clinics, there is evidence that patients managed in anticoagulation management clinics are within the targeted INR a larger percentage of the time. Therefore, a decrease in the incidence of thromboembolism and the incidence of major bleeding would be expected [45]. Cost analysis based on the data from a number of reports comparing routine medical care with anticoagulation management clinics indicate that anticoagulant management clinics are capable of achieving cost savings that should be equal to the cost of running the clinics themselves. Computer programs are available for managing data for anticoagulant management clinics, and one system has been developed for the ongoing prescribing of warfarin once patients have a stable INR on at least two occasions. In an interesting report, it was shown that the computer was superior to experienced hematologists in ordering warfarin, with a higher percentage of patients achieving their targeted INR a greater amount of time with the use of the computer program [46]. Point of care International Normalized Ratio testing A number of instruments are available for measuring capillary INRs on finger sampling of whole blood. INRs performed with these instruments compare well with venous samples, and numerous studies have indicated that many patients are capable of self-testing and self-management of their warfarin dosing [47], [48], [49]. Indeed, some studies have indicated that self-management of warfarin therapy using point-of-care INR testing has resulted in higher INR compliance with fewer tests when compared with physician managed patients [49]. Clinical uses of oral anticoagulants Long-term treatment of venous thromboembolism Patients with established venous thrombosis or pulmonary embolism require long–term anticoagulant therapy to prevent recurrent disease [50], [51]. Warfarin therapy is highly effective and is preferred in most patients. Adjusted–dose subcutaneous heparin is the treatment of choice where long–term oral anticoagulants are contraindicated, such as in pregnancy [51]. Adjusted–dose subcutaneous heparin, or unmonitored low–molecular-weight heparin has been used for the long-term treatment of patients in whom oral anticoagulant therapy proves to be very difficult to control [52]. In patients with proximal vein thrombosis, long-term therapy with warfarin reduces the frequency of objectively documented recurrent venous thromboembolism from 47% to 50%. The use of a less intense warfarin regimen (INR 2 to 3) markedly reduces the risk of bleeding from 20% to 4%, without loss of effectiveness compared with more intense warfarin [16]. With the improved safety of oral anticoagulant therapy using a less intense warfarin regimen, there has been renewed interest in evaluating the long-term treatment of thrombotic disorders. Optimal duration of treatment after a first episode of deep vein thrombosis It has been recommended that all patients with a first episode of venous thromboembolism receive warfarin therapy for at least 3 to 6 months. Attempts to decrease the treatment to 4 [53], [54] or 6 weeks [55] have resulted in higher rates of recurrent thromboembolism compared with either 12 or 24 weeks of treatment (11% to 18% recurrent thromboembolism in the following 1 to 2 years). Most of the recurrent thromboembolic events occurred in the 6 to 8 weeks immediately after anticoagulant treatment was stopped, and the incidence was higher in patients with continuing risk factors, such as cancer and immobilization [55]. Treatment with oral anticoagulants for 6 months reduced the incidence of recurrent thromboembolic events, but there was a cumulative incidence of recurrent events at 2 years (11%) and an ongoing risk of recurrent thromboembolism of approximately 5% to 6% per year [55]. In patients with a first episode of idiopathic venous thromboembolism treated with intravenous heparin followed by warfarin for 3 months, continuation of warfarin for 24 months led to a significant reduction in the incidence of recurrent venous thromboembolism compared with placebo [56]. In a further recent trial comparing 3 months oral anticoagulant therapy with 12 months of therapy after the occurrence of a first episode of idiopathic proximal deep venous thrombosis, it was shown that patients only treated for 3 months had a higher incidence of recurrence of venous thromboembolism during the subsequent 12 months compared with those patients who continued on anticoagulants for 12 months [57]. The cumulative hazard of recurrent venous thromboembolism at 36 months was the same in both groups, however. The incidence of recurrence after discontinuation of treatment was 5.1% per patient year in patients where oral anticoagulant therapy was discontinued after 3 months and 5% per patient year in patients who received an additional 9 months of oral anticoagulant therapy. The recurrence occurred in the initially unaffected leg more than 50% of the time. This suggested that the recurrences were related to a hypercoagulable state, and the duration of anticoagulant therapy did not influence the ultimate recurrence rate. Venous thromboembolism should be considered a chronic disease with a continued risk of venous thromboembolism often associated with minor provocation [58]. The continued risk of recurrent thromboembolism even with 12 months treatment after a first episode of deep vein thrombosis has encouraged the development of clinical trials evaluating the effectiveness of long-term anticoagulant treatment beyond 6 months. Clinical trials are underway to determine if long-term treatment of anticoagulation with a targeted of INR of 1.5 to 2.0 can decrease the incidence of recurrent thromboembolism without an increase in major bleeding when compared with a targeted INR of 2.0 to 3.0 or to placebo treatment. It will be a few years before the results of these clinical trials are available. Optimal duration of treatment in patients with recurrent deep vein thrombosis In a multicenter clinical trial, Schulman et al randomized patients with a first recurrent episode of venous thromboembolism, to receive either 6 months or continued oral anticoagulants indefinitely, with a targeted INR of 2.0 to 2.85 [59]. The analysis was reported at 4 years. In patients receiving anticoagulants for 6 months, recurrent thromboembolism occurred in 20.7% of patients, compared with 2.6% of patients in the indefinite treatment (P < 0.001) group. Rates of major bleeding were 2.7%, however, in patients treated for 6 months, compared with 8.6% among patients treated indefinitely. Among patients treated indefinitely, two of the major hemorrhages were fatal, whereas there were no fatal hemorrhages among patients treated for 6 months. This study showed that extending the duration of oral anticoagulants for approximately 4 years resulted in a significant decrease in the incidence of recurrent venous thromboembolism, but with an increased incidence of major bleeding. Without a mortality difference, the risk of hemorrhage versus the benefit of decreased recurrent thromboembolism with the use of extended warfarin treatment remains uncertain and will require further clinical trials. The sixth ACCP Consensus Conference on Antithrombotic Therapy made several recommendations [51]. Oral anticoagulant therapy should be continued for at least 3 months to prolong the PT to a targeted INR of 2.5 (range, 2 to 3). Patients with reversible or time-limited risk factors can be treated for 3 to 6 months. Patients with a first episode of idiopathic venous thromboembolism should be treated for at least 6 months. Please note that these recommendations antedated the results of the Agnelli study [57]. Patients with recurrent venous thromboembolism or continuing risk factors such as cancer, antithrombin deficiency states, or antiphospholipid syndrome should be treated indefinitely. Patients with activated protein C resistance (factor V Leiden) probably should receive indefinite treatment if they have recurrent disease, are homozygous for the gene, or have multiple thrombophilic conditions. Accumulated evidence indicates that symptomatic isolated calf vein thrombosis should be treated with anticoagulants for at least 3 months [51]. Preventing venous thromboembolism The use of oral anticoagulants treatment with a targeted INR of 2 to 3 is effective at preventing venous thrombosis following hip fracture or total hip or total knee replacement [60]. Recent studies, however, have demonstrated that the use of low–molecular-weight heparin in close proximity to surgery is more effective than oral anticoagulants following total hip replacement [61]. Preventing ischemic stroke in patients with atrial fibrillation Researchers compared the efficacy and safety of warfarin with aspirin treatment in five randomized clinical trials in patients with atrial fibrillation [62], [63], [64], [65], [66]. In all studies, warfarin was superior to aspirin for preventing ischemic stroke, and there was little difference in the rate of major or intracranial bleeding [62], [63], [64], [65], [66]. Minor bleeding was seen more frequently with warfarin treatment. The European Atrial Fibrillation Trial compared the anticoagulant treatment, aspirin, and placebo for preventing ischemic stroke in patients with atrial fibrillation [67]. Compared with placebo, there was a significant decrease in the incidence of stroke with warfarin but an insignificant difference in risk reduction with aspirin. In the Stroke Prevention in Atrial Fibrillation III trial, adjusted-dose warfarin with a targeted INR of 2 to 3 was more effective than a fixed dose of warfarin (1 mg to 3 mg/day) plus aspirin (325 mg/day) in patients with atrial fibrillation at high risk of embolism. Aspirin alone was sufficient in patients with atrial fibrillation at low risk of thromboembolism [68]. Researchers recently reviewed the Cochrane Database systematically to determine the benefit and risk of warfarin versus placebo or aspirin in patients with nonrheumatic atrial fibrillation [69]. They concluded that warfarin prevented stroke among those patients with average or higher risk and was more effective than antiplatelet drugs. The risk of major hemorrhage was increased with warfarin, however. Warfarin should be considered in all patients with chronic atrial fibrillation, and the risk benefits of such treatment should be assessed. Aspirin treatment should be used only in patients with a contraindication to warfarin. For patients requiring ongoing anticoagulation, for example with atrial fibrillation, who experience bleeding while on warfarin, another suggested option is to use anticoagulant treatment with a target INR of 1.5 to 2 with the expectation that the bleeding risk may be less but that efficacy probably will be reduced [23]. Despite the benefits of warfarin for preventing stroke in patients with atrial fibrillation, it is disappointing that only 15% to 44% of patients with atrial fibrillation who have no contraindication to the therapy actually receive warfarin treatment [70]. Long-term anticoagulation in patients with cardiovascular disorders Oral anticoagulants have been used in the primary or secondary prevention of myocardial infarction and in patients with a variety of prosthetic heart valves. Low-intensity warfarin plus aspirin has been compared with aspirin alone in the primary prevention of acute ischemic coronary events (ie, death or nonfatal myocardial infarction). In the CARS study (Coumadin Aspirin Reinfraction Study), fixed low-dose intensity warfarin was similar to aspirin for preventing death or myocardial infarction [71]. In the Thrombosis Prevention Trial, adjusted-dose warfarin with a targeted INR of 1.3 to1.8 plus aspirin was compared with aspirin alone for preventing death or myocardial infarction [72]. The combination of warfarin and aspirin was effective in reducing these outcomes, whereas either warfarin or aspirin given alone did not produce a significant reduction in these endpoints. In these low-intensity warfarin studies, it is apparent the dose of warfarin needs to be adjusted to an INR of at least 1.5 when combined with aspirin in order to achieve a therapeutic benefit. The multitude of clinical trials comparing warfarin of varying intensities with either placebo or aspirin was reviewed recently in a meta-analysis [73]. From this analysis, it was shown that moderate-to-high–intensity warfarin was more effective than either aspirin or placebo but with an increased incidence of major bleeding. Although low fixed-dose unmonitored warfarin plus aspirin was more effective than aspirin, it produced an increase in major bleeding. Moderately intense warfarin plus aspirin was superior to aspirin alone with only a marginal and nonsignificant increase in major bleeding. Warfarin has been used for preventing thromboembolic events in patients with a variety of prosthetic heart valves [40]. The data are reviewed in the recent Consensus Conference of the ACCP [40]. In general, warfarin with a targeted INR of 2.5 to 3.5 is recommended for most patients with mechanical prosthetic valves. An INR of 2 to 3 is recommended with bioprosthetic valves and low-risk patients with bileaflet mechanical valves in the aortic position. A recent meta-analysis explored the risk and benefits of adding antiplatelet therapy to warfarin among patients with prosthetic heart valves [74]. 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Foothills Hospital, 601 South Tower 1403-29 Street, NW, Calgary, Alberta T29 2T9, Canada  Corresponding author
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