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• W2021103066 abstract "Since the early reports on the efficacy of anticoagulant therapy,1,2 the use of these agents has expanded to include numerous indications (Table I). It is estimated that at any given time approximately 3 million patients in the U.S. are using warfarin, and 22.5 million prescriptions for warfarin were filled in 1999. Despite the demonstrated efficacy of warfarin in preventing venous, and in many instances arterial, thrombosis and thromboembolism, concerns remain regarding potential complications, precise indications, length of administration, intensity and frequency of monitoring, and underutilization. The American College of Chest Physicians has held consensus conferences on antithrombotic therapy since 1985 and publishes the results in the journal Chest. The latest report,3 published in 1998, is an excellent and comprehensive guideline that includes almost all available evidence regarding the use of these agents. Similarly, the American Heart Association and the American College of Cardiology have prepared a guide to oral anticoagulant therapy.4 Both of these documents provide all the essential information to allow the practitioner to prescribe and monitor oral and parenteral anticoagulant therapies safely and effectively. This brief review addresses some of the current issues regarding the use of oral anticoagulants. Warfarin is the most commonly used oral anticoagulant in the U.S. An injectable preparation is available but rarely used. Warfarin inhibits the synthesis of the vitamin K-dependent clotting factors II, VII, IX, and X and impairs the function of the regulatory anticoagulant proteins C and S. It has a high bioavailability and is absorbed rapidly from the gastrointestinal tract, reaching maximal serum concentrations 90 minutes after oral administration. The relationship between warfarin dose and its anticoagulant effect is influenced by environmental and genetic factors, including a recently described mutation in the gene coding for cytochrome P450. It is likely that this mutation is responsible for the variability of dose response to warfarin among healthy subjects.5 It is well recognized that certain drugs (Table II), dietary variations, and various disease states also can influence the response to warfarin. Patients on chronic warfarin therapy are sensitive to fluctuating levels of dietary vitamin K. Such fluctuations in vitamin K intake have been noted in both healthy subjects and sick patients. Increased intake of vitamin K sufficient to reduce the anticoagulant effect of warfarin is often seen in patients on weight reduction diets, which usually include a large amount of green vegetables or vitamin K-containing dietary supplements. Conversely, reduced dietary intake of vitamin K potentiates the anticoagulant effect of warfarin in sick patients being treated with i.v. fluids and antibiotics, and in patients with fat malabsorption. In order to limit the effects of dietary fluctuations, a diet with constant vitamin K content has been proposed.6 Severe liver disease with disturbed hepatic synthetic function potentiates the response to warfarin through impaired synthesis of coagulation factors. Hyperthyroidism and other hypermetabolic states increase the responsiveness to warfarin by increasing the catabolism of vitamin K-dependent coagulation factors. Increased monitoring surveillance is necessary when any of the above situations develops, in order to adjust the warfarin dosage and maintain the anticoagulant effect in a desired range. The prothrombin time (PT) is the test used to monitor oral anticoagulant therapy. The PT reflects the reduction of factors II, VII, and X induced by warfarin at a rate that reflects their half-lives. In the first few days after initiation of warfarin therapy, the PT reflects mainly reduction of factor VII, which has a half-life of 6 hours. Later, a reduction of factors X and II contributes to the prolongation of the PT. The full anticoagulant effect of warfarin is usually observed within 3–7 days after therapy is begun, depending on the dose administered. When rapid anticoagulation is the goal, heparin should be given concurrently with warfarin for at least 4 days. The practice of administering an initial “loading” dose of warfarin is usually unnecessary, and has been largely abandoned. Starting therapy with an average maintenance dose of 5 mg daily will usually result in a therapeutic PT with an international normalized ratio (INR) of 2 (see below) after 4 or 5 days. Heparin can be discontinued once the PT has been in the therapeutic range for 2 days. In nonurgent cases (e.g., chronic atrial fibrillation), treatment can be started in the outpatient setting with a warfarin dose of 4–5 mg daily and without concurrent heparin. This will usually prolong the PT to within the therapeutic range within 6 days. Beginning doses lower than 4 or 5 mg daily should be prescribed to patients sensitive to warfarin, the elderly, and those at increased risk of bleeding. Until the late 1980s, monitoring of warfarin therapy was imprecise because the PT was expressed in seconds or as a simple ratio of the patient's plasma over the normal control plasma value. Furthermore, most laboratories in the U.S. used insensitive thromboplastins, whereas many laboratories in Europe used more sensitive reagents. This resulted in clinically important differences in warfarin dosing in different countries. Recognition of the clinical importance of these differences has led to the adoption of the INR, which is calculated as follows: INR=(patient PT/mean normal PT)ISI, where ISI is the International Sensitivity Index of thromboplastin used to perform the PT measurement. Thus, the INR reflects what the PT ratio would have been if the World Health Organization reference thromboplastin had been used for the determination. A number of studies have demonstrated that for most indications optimal anticoagulation is achieved with an INR range of 2–3. A higher INR range of 2.5–3.5 is recommended for certain mechanical valve prostheses in the aortic position (e.g., Starr-Edwards), for all mechanical prostheses in the mitral position, and for bioprosthetic valves in the mitral position in patients with high thromboembolic risk (e.g., atrial fibrillation, hypercoagulable states).7 A higher INR range is also recommended for patients with thrombotic episodes secondary to the antiphospholipid syndrome and, recently, for postmyocardial infarction patients.8 The practitioner should keep in mind, however, that a strong relationship exists between intensity of anticoagulant therapy and the risk of hemorrhagic complications.9 No precise guidelines regarding the frequency of PT (INR) monitoring are available. Empiric practice suggests that the PT should be checked daily until the therapeutic range has been achieved and maintained for 2 consecutive days, then 2 or 3 times weekly for 1–2 weeks, and then less frequently depending on the stability of the results. In patients with stable PT determinations, testing can be stretched to monthly intervals. If adjustments to warfarin dose are required, more frequent PT testing should be again performed. The frequency of PT testing should also increase if a patient develops an intercurrent illness or is prescribed antibiotics or other drugs known to interact with warfarin, or if major dietary changes are anticipated. By far, the most common indication for warfarin therapy today is chronic, nonrheumatic atrial fibrillation. Five randomized, controlled trials in the past decade demonstrated a significant reduction in the risk of cardioembolic stroke in patients with atrial fibrillation when warfarin was compared to placebo (69% risk reduction from pooled data). Three studies in which patients were randomized to aspirin or warfarin demonstrated that aspirin resulted in an insignificant risk reduction compared to warfarin, whereas a fourth study showed a statistically significant 42% risk reduction with aspirin. Combining the results of these studies, the data indicate that aspirin therapy also results in a small but significant reduction in the risk of stroke in patients with atrial fibrillation. Four studies directly compared the efficacy of aspirin with oral anticoagulation. The overall results indicate that the risk reduction associated with warfarin is considerably greater than that provided by aspirin. Risk stratification of patients with nonrheumatic atrial fibrillation has shown that the following risk factors are associated with an increased risk of stroke: prior transient ischemic attacks (TIAs), prior stroke, history of hypertension, systolic blood pressure >160 mm Hg, diabetes mellitus, impaired left ventricular systolic function, and advanced age (especially in women over the age of 75 years). This risk stratification combined with the results of the above mentioned trials form the basis of current recommendations for anticoagulation therapy in patients with atrial fibrillation (Table III). The question frequently arises whether patients with atrial flutter require similar anticoagulation therapy, especially at the time of cardioversion. In general, atrial flutter is an unstable rhythm that frequently devolves into atrial fibrillation. It is, therefore, prudent to treat patients with atrial flutter in the same manner as patients with atrial fibrillation. Elective direct current cardioversion is frequently employed to convert atrial fibrillation to sinus rhythm. In a prospective, nonrandomized cohort study, Bjerkelund and Orning10 demonstrated a significant reduction of embolic events in patients receiving anticoagulant therapy compared to those not on therapy (0.8% vs. 5.3%). On the basis of this and other observational reports with equally compelling results, the current practice is to use anticoagulant therapy prior and following cardioversion. It is estimated that an atrial thrombus, once formed, takes approximately 2 weeks to become firmly adherent so that it will not break free or fragment when atrial contractions resume. Similarly, postcardioversion, forceful mechanical contractions of the atrial appendage may not resume for 2–4 weeks. These observations have led to the recommendations that elective cardioversion be preceded by a 3-week period of warfarin anticoagulation (INR 2–3), and that anticoagulation be continued for 4 weeks after cardioversion. Although no controlled trials are available, several instances of embolization following cardioversion of patients with pure atrial flutter have been reported. Because of these reports and the frequent alternation between atrial flutter and atrial fibrillation, it is recommend that a similar anticoagulation regimen be followed in both atrial flutter and atrial fibrillation. Several investigators have recently reported that transesophageal echocardiography (TEE) may be used to exclude the presence of atrial appendage thrombus prior to cardioversion, thereby, reducing the need for 3 weeks of precardioversion anticoagulation. A discussion of the advantages and disadvantages of this approach is beyond the scope of this review. However, the point must be made that the absence of an appendage thrombus does not eliminate the risk of thrombus formation after cardioversion until atrial mechanical function returns. Therefore, anticoagulation for 4 weeks following cardioversion is strongly recommended, even in the presence of a negative TEE. There have been no clinical trials that have examined the problem of embolization after pharmacologic cardioversion of atrial fibrillation to sinus rhythm. Goldman11 reported a 1.5 % incidence of embolism in 400 patients treated with quinidine for conversion of atrial fibrillation. This is similar to the 1.2 % incidence of embolization reported by Lown12 after electric cardioversion in patients not receiving anticoagulants. It appears reasonable, therefore, to prescribe anticoagulants to patients undergoing pharmacologic cardioversion in the same manner as to patients undergoing electric cardioversion. The incidence of systemic embolization is greater in rheumatic mitral valve disease than in any other form of valvular heart disease, and rises dramatically with the development of atrial fibrillation. Systemic emboli occur 1.5 times as frequently in rheumatic mitral stenosis as in rheumatic mitral regurgitation. The risk of systemic embolization in rheumatic mitral valve disease is greater in older patients and those with low cardiac output but correlates poorly with valvular calcification, mitral orifice area, or functional class. Other than advancing age and atrial fibrillation, there are no reliable markers of increased risk for systemic embolization in mitral valve disease. Some investigators have suggested that patients with a very large left atrium (>55 mm) should receive anticoagulant therapy, since their potential for developing atrial fibrillation is high. Current recommendations are to use long-term warfarin therapy (INR 2–3) in patients with rheumatic mitral valve disease who: 1) have a history of systemic emboli or paroxysmal atrial fibrillation, and 2) are in sinus rhythm but have a left atrial dimension of >55 mm. Mitral valve prolapse (MVP) is uncommonly associated with systemic embolization. Given the large number of individuals with this disorder, the incidence of thromboembolism is thought to be extraordinarily low. Current recommendations are for chronic warfarin anticoagulation (INR 2–3) to be prescribed for patients with MVP who have had documented systemic emboli, chronic or paroxysmal atrial fibrillation, or recurrent TIAs despite aspirin therapy. Patients with MVP and documented but unexplained TIAs, who do not fall into one of the above categories, should be treated with aspirin (160–325 mg daily). Asymptomatic patients with MVP should not be treated with antithrombotic agents. Convincing evidence has emerged over the past two decades noting that oral anticoagulant therapy effectively reduces the incidence of embolic complications in patients with prosthetic cardiac valves. Furthermore, in one study13 patients treated with warfarin had a significantly lower incidence of emboli than patients on antiplatelet regimens. More recent studies have investigated the efficacy of oral anticoagulant therapy of various intensities, as well as the combination of warfarin and aspirin, in preventing embolic complications in patients with prosthetic cardiac valves. The European Society of Cardiology proposed that the intensity of anticoagulant therapy be proportionate to the thromboembolic risk of the specific type of prosthetic valve. The American College of Chest Physicians and the Practice Guidelines Task Force of the American College of Cardiology and the American Heart Association have promulgated guidelines regarding current recommendations for anticoagulant therapy in this group of patients (Table IV). Management of anticoagulation during pregnancy is difficult. All anticoagulants can cause potential complications in both mother and fetus. Particularly difficult is the management of pregnant women with mechanical prosthetic valves, since they require uninterrupted anticoagulant therapy throughout pregnancy. Warfarin can cause embryopathy, particularly if taken between 6 and 12 weeks of gestation. In addition, because warfarin crosses the placenta, it may cause fetal bleeding as a result of delivery trauma. Heparin, heparinoids, and low molecular weight heparins do not cross the placenta and, therefore, do not cause embryopathy or fetal bleeding, although bleeding at the uteroplacental junction is possible. In the absence of randomized, controlled trials, various anticoagulant regimens have been proposed, none of which is wholly satisfactory. Prosthetic valve thrombosis during adjusted-dose subcutaneous heparin therapy has been reported, but the adequacy of the heparin dose in these cases has been questioned. Other investigators suggest that the risk of warfarin-induced embryopathy has been exaggerated, and recommend warfarin therapy throughout pregnancy until near term, when heparin is substituted. However, warfarin is not approved by the FDA for use during pregnancy. Therefore, the following approach is recommended for pregnant women with prosthetic cardiac valves. In a planned pregnancy, warfarin is stopped and adjusted-dose subcutaneous heparin is started from conception and continued until the end of the first trimester; the patient is then given a choice of continuing adjusted-dose subcutaneous heparin or resuming warfarin anticoagulation. Near term, warfarin is stopped and intravenous heparin anticoagulation is begun; it is stopped at the onset of labor. Two hours following delivery, i.v. heparin therapy is resumed, and warfarin therapy is restarted at 24 hours postpartum. Intravenous heparin is continued until the INR is in the therapeutic range for 2 days. In cases of unplanned pregnancy, warfarin should be stopped immediately—if possible, before 6 weeks of gestation. Adjusted-dose subcutaneous heparin is then given until the end of the first trimester. From then, the therapeutic regimen proceeds as described above for planned pregnancy. The major complication of chronic oral anticoagulant therapy is bleeding, and the major determinants of oral warfarin-induced bleeding are the intensity of the anticoagulation regimen, patient characteristics, the use of drugs that interfere with hemostasis, and the length of therapy. A strong relationship between the intensity of anticoagulant therapy and the risk of bleeding has been reported in patients with deep venous thrombosis and prosthetic cardiac valves. In randomized trials, the frequency of hemorrhagic complications in patients receiving warfarin therapy with a target INR of 2–3 was less than one half the frequency of hemorrhage in patients randomly assigned to more intense warfarin therapy (INR >3.0). Furthermore, the intensity of anticoagulant therapy is probably the most important risk factor for intracranial hemorrhage—the most dreaded complication of anticoagulant therapy. This risk increases dramatically when the INR exceeds 4. In terms of patient characteristics, observational studies suggest that the risk of bleeding is related to age, history of prior bleeding episodes, and certain comorbid conditions. Several studies disclosed that the frequency of bleeding during oral warfarin therapy is higher in older patients, although other studies have not shown this. Of the five cohort studies recently reported, in four the frequency of bleeding was higher in older patients and in one this was not the case.14 Other studies have found that the risk of intracranial hemorrhage may be increased among older patients, especially those over the age of 75 years.15,16, However, a recent analysis of the SPAF2 study, which reported a 4.2% incidence of major bleeding events in patients over 75 years of age, confirms that major hemorrhagic complications were significantly related to high intensity anticoagulation as well as to age. These findings create a major dilemma for the elderly patient with atrial fibrillation, who is at highest risk for cardioembolic stroke. The results of the six major randomized trials of warfarin vs. placebo in patients with atrial fibrillation suggest that the net benefit of anticoagulant therapy exceeds the risk of major bleeding in the over 75 year group, and form the basis for the recommendations that have been listed previously." @default.
• W2021103066 created "2016-06-24" @default.
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• W2021103066 date "2000-09-01" @default.
• W2021103066 modified "2023-09-23" @default.
• W2021103066 title "Oral Anticoagulant Therapy: Current Issues" @default.
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