and enteral nutrition. Moxalactam disodium products). Neomycin suHate. Trimethoprim-sulfamethoxazole. Cimetidine. Clofibrate. Disulfiram. Phenylbutazone.
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Long-term Anticoagulation Indications and Management BARRY M. STULTS, MD; WILLARD H. DERE, MD; and THOMAS H. CAINE, MD, Salt Lake City
Each year half a million persons in the United States receive long-term anticoagulant therapy to prevent venous and arterial thromboembolism. Unfortunately, the relative benefits and risks of anticoagulant therapy have not been adequately quantified for many thromboembolic disorders, and the decisions as to whether, for how long, and how intensely to administer anticoagulation are often complex and controversial. Several expert panels have published recommendations for anticoagulant therapy for different thromboembolic disorders; the primary area of disagreement among these panels concerns the optimal intensity of anticoagulation. Recent research and analytic reviews have helped to clarify both the risk factors for and the appropriate diagnostic evaluation of anticoagulant-induced hemorrhage. Clinicians must be aware of the nonhemorrhagic complications of anticoagulant therapy, particularly during pregnancy. The administration of anticoagulants is difficult both in relation to dosing and long-term monitoring. Knowledge of the pharmacology of the anticoagulants, an organized approach to ongoing monitoring, and thorough patient education may facilitate the safe and effective use of these drugs. (Stults BM, Dere WH, Caine TH: Long-term anticoagulation-Indications and management. West J Med 1989 Oct; 151:414-429) bout 500,000 persons annually in the United States receive anticoagulants for the treatment and prophylaxis of thromboembolic disorders.1 2 The most common indications for long-term anticoagulant therapy in recent years A
have been venous thromboembolism, valvular heart disease (especially prosthetic heart valves), atrial fibrillation, and ischemic cerebrovascular disease.`~Patients anticoagulated long term are usually middle-aged or elderly; in two recent series, their average age was 55 to 60 years, and 25 % to 30 % were older than 70 years.4'5 They frequently have chronic illnesses in addition to their thromboembolic disorder; in one review of patients attending a university hospital anticoagulation clinic, 25 % had three or more medical problems, and nearly 70% took three or more medications in addition to anticoagulants.4 Anticoagulant therapy, especially in patients with coexisting chronic illness and taking several medications, is associated with considerable morbidity and some mortality from hemorrhage. As a result, the decision to anticoagulate an individual patient is often complex and sometimes controversial. Clinicians must attempt to estimate the benefit:risk ratio for each patient by considering the following variables6: * The rate, morbidity, and mortality of thromboembolism without anticoagulation; * The expected reduction in rate of thromboembolism with anticoagulation; * The rate, morbidity, and mortality of anticoagulantinduced complications, especially hemorrhage; * The following effects of anticoagulant therapy on a patient's quality of life: The economic costs of medications, laboratory tests, clinic visits, and complications;
Any required alterations in life-style or occupation; Anxiety that may be engendered in some patients by anticoagulant therapy. Unfortunately, for most thromboembolic disorders, available data do not adequately quantify these variables. Moreover, the benefits and risks of anticoagulant therapy may vary considerably among different patients and in the same patient over time. 6 Despite these uncertainties, clinicians must still decide whether and how to anticoagulate their patients. To facilitate making more rational clinical decisions, several groups of experts have recently analyzed the available evidence on the indications for and complications associated with long-term anticoagulant therapy.7-12 We review their conclusions and recommendations, updating them when appropriate, and describe techniques for determining the optimal administration of anticoagulants. First, however, it is important to summarize the basic pharmacology and laboratory monitoring of anticoagulants.
Pharmacology and Laboratory Monitoring of Anticoagulants The use of warfarin sodium, a vitamin K antagonist, leads to the synthesis of biologically inactive forms of clotting factors II, VII, IX, and X. The one-stage prothrombin time (PT) is sensitive to three of these four vitamin K-dependent factors and is used to monitor the effects of warfarin therapy. It may be expressed as the prothrombin time ratio: patient time in seconds per normal control time in seconds. The serum half-lives of these clotting factors vary from four to six hours for factor VII to two to three days for factors II and X. While large doses of warfarin may increase the PT ratio
From the Division of General Internal Medicine, University of Utah Medical Center, and Veterans Administration Medical Center, Salt Lake City. Reprint requests to Barry M. Stults, MD, Division of General Internal Medicine, University of Utah Medical Center, 50 N Medical Dr, Salt Lake City, UT 84132.
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ABBREVIATIONS USED IN TEXT ACCP = American College of Chest Physicians DVT = deep venous thrombosis INR = international normalized ratio ISI = international sensitivity index MI = myocardial infarction NHLBI = National Heart, Lung, and Blood Institute PT = prothrombin time PTT = partial thromboplastin time WHO = World Health Organization
within 24 hours due to a suppression of factor VII, maximal depression of the activities of factors II and X-and therefore the maximal antithrombotic effect-is delayed for as long as five to seven days. 3 Warfarin therapy also inhibits synthesis of the anticoagulant proteins C and S, which are important in preventing thrombosis on the surface of platelets and vascular endothelium. 13 Because protein C has a short half-life similar to that of factor VII, the first few days of warfarin therapy may theoretically constitute a period of relative hypercoagulability, as the anticoagulant activity of protein C decreases before the procoagulant activity of factors II, IX, and X. These events may have pathophysiologic importance for the rare complication of warfarin-induced skin necrosis discussed later. 14 The use in North America and Europe of different thromboplastins to measure the PT ratio has resulted in some confusion.2 Rabbit brain thromboplastins are used in most North American centers, and human brain thromboplastins have been used in Europe. Human brain thromboplastins are more responsive to the reduction in vitamin K-dependent clotting factors, resulting in a significantly greater PT ratio compared with that in the same plasma specimen tested with a rabbit brain preparation. To limit confusion, the World Health Organization (WHO) has recommended that all PT ratio measurements worldwide undergo a standard correction and be expressed during long-term maintenance therapy as the "international normalized ratio" (INR)." 2 The INR is the PT ratio that would be observed if the plasma specimen were tested with the WHO reference thromboplastin originally derived from human brain. The PT ratio measured with any local thromboplastin can be converted to the corresponding INR using the equation: INR = observed PT ratio1s5, where ISI is the "international sensitivity index" specific to the particular thromboplastin. 1 The ISI is a measure of the particular thromboplastin's responsiveness to the reduction of vitamin K-dependent coagulation factors. The WHO reference thromboplastin has an ISI of 1.0; the ISI increases as thromboplastins become less responsive. It has been proposed that all thromboplastin manufacturers calibrate their reagents against the WHO reference thromboplastin and provide local laboratories with the resulting ISI, so that they can express locally measured prothrombin time ratios as the in-
TABLE 1.-Equivalent Prothrombin Time (PT) Ratios for North American Rabbit Brain and International Normalized Ratio (INR) Reference Thromboplastins* INR
2.0-3.0 3.0-4.5
Corresponding Rabbit Brain PT Ratios ISI=2.6 ISI=2.0 ISI=2.3
1.4-1.7 1.7-2.1
ISI=international sensitivity index *Modified from Hirsh and Levine.2
1.4-1.6 1.6-1.9
1.3-1.5 1.5-1.8
ternational normalized ratio using a simple nomogram.2 " Most ISI values for rabbit brain thromboplastins in North America are between 2.0 and 2.6.2 Table 1 lists the PT ratio ranges of rabbit brain thromboplastins with ISI values of 2.0, 2.3, and 2.6 along with the equivalent INR ranges. Few North American laboratories currently express PT ratios as the INR.2 It is notable that the reliability of this system for converting locally measured PT ratios to the INR system during the first few weeks of coumarin drug administration has recently been questioned.'6 Subsequent PT ratios in this article are uncorrected measurements using a rabbit brain thromboplastin with an ISI of approximately 2.4, as recently used by a national task force on anticoagulation therapy.8 Subcutaneous heparin may be used as an alternative to warfarin for long-term anticoagulation in selected patients with venous thromboembolism"7 and for pregnant women with prosthetic heart valves. 12 Heparin augments the inhibition by antithrombin III of several activated coagulation factors but has no effect on the production of these factors. Therefore, in contrast to those of warfarin, the antithrombotic effects of heparin occur immediately but also begin to decline about 12 hours or longer after cessation of subcutaneous administration, depending on the dose.'7 Heparin therapy is generally monitored by the activated partial thromboplastin time (PTT), although in selected patients measuring whole blood heparin levels with protamine titration may be helpful. 18
Indications for Long-term Anticoagulation Expert panels have recently published recommendations for anticoagulant therapy for thromboembolic disorders, including indications for use and the appropriate intensity and duration of therapy.7'2 The recommendations of the task force of the American College of Chest Physicians (ACCP) and the National Heart, Lung, and Blood Institute (NHLBI), originally published in 19867 and updated with several modifications in 1989,8 are reproduced in Table 2; they include an estimate of the relative strength of scientific evidence supporting each recommendation. The primary controversy among the various expert recommendations relates to the intensity of anticoagulation for different thromboembolic disorders. The ACCP-NHLBI task force recommends the use of low-intensity warfarin to a PT ratio of i.3 to 1.5-a prothrombin time of about 15 to 18 seconds-for all thromboembolic disorders except mechanical prosthetic heart valves, bioprosthetic mitral valves with associated atrial fibrillation or left atrial thrombi for the first three months after a valve replacement operation, and recurrent systemic embolism; for these disorders they suggest a conventional warfarin regimen to a PT ratio of 1.5 to 2.0-a prothrombin time of about 18 to 24 seconds. If there is no recurrence of systemic embolism after a year of warfarin therapy to a PT ratio of 1.5 to 2.0, those patients who do not have mechanical heart valves may have the intensity of warfarin therapy reduced to a PT ratio of 1.3 to 1.5; patients with mechanical heart valves should continue to receive conventional-intensity warfarin therapy. There is evidence from randomized, controlled trials supporting the efficacy of lowintensity warfarin for the treatment of venous thromboembolism after an initial course of heparin,'9 the prevention of cardioembolism during the first three months after bioprosthetic heart valve replacement,20 and short-term (one month) prevention of cardioembolism and venous thrombo-
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embolism following acute myocardial infarction.2 22 In the two trials that directly compared the two intensities of anticoagulation, low-intensity warfarin therapy was associated with twofold20 and fourfold"9 lower rates of hemorrhagic complications than conventional warfarin therapy. In contrast, evidence for the other recommendations in Table 2 for
the use of either low- or conventional-intensity warfarin is considerably weaker, coming from nonrandomized trials, case studies, or both.8 Pending further studies, some expert groups, therefore, recommend conventional-intensity warfarin therapy for all thromboembolic disorders other than venous thromboembolism. 10'12
TABLE 2.-Recommendations for Long-term Anticoagulation* Thromboembolic Disorder
Recommended Prothrombin Time (PT) Ratio
Venous thromboembolism Proximal deep venous thrombus (DVT) or pulmonary embolus ... 1.3-1.5 Isolated symptomatic caH DVT
1.3-1.5
Chronic atrial fibrillation (AF) With cardioembolic stroke .
1.5-2.0 for 1 year, then 1.3-1.5 With valvular heart disease ..... 1.3-1.5 With idiopathic dilated and hypertrophic cardiomyopathies ...... 1.3-1.5 With thyrotoxicosis ...... .... 1.3-1.5
With coronary, hypertensive, or congenital heart disease, in selected patients, especially when complicated by heart failure .... 1.3-1.5
Idiopathic AF without associated heart disease (lone AF) Older than 60, selected patients 1.3-1.5 Younger than 60 ...... ... No therapy Cardioversion of atrial fibrillation ... 1.3-1.5
Valvular heart disease Mitral regurgitation or stenosis With cardioembolic stroke . 1.5-2.0 for 1 year, then 1.3-1.5 With chronic or paroxysmal AF 1.3-1.5 With enlarged left atrium (diameter >55 mm) and sinus rhythm ........ .... 1.3-1.5 Mitral valve prolapse With cardioembolic stroke . 1.5-2.0 for 1 year, then 1.3-1.5 With AF or recurrent transient cerebral ischemia refractory to aspirin therapy .......... 1.3-1.5 Mechanical prosthetic heart valves 1.5-2.0 Bioprosthetic heart valves Mitral position, sinus rhythm . 1.3-1.5 Mitral position with AF or left atrial thrombi ........ 1.5-2.0 for first 3 months after replacement, then 1.3-1.5 Acute myocardial infarction (Ml) Transmural anterior acute Ml, 1.3-1.5 or large inferior acute Ml with heart failure or AF ........... 1.3-1.5 After acute Ml with severe heart failure, AF, or previous venous thromboembolism .... . 1.3-1.5 1.3-1.5 Idiopathic dilated cardiomyopathy Prevention of recurrent cardioembolism .............. 1.5-2.0 for 1 year, then 1.3-1.5
Duration of Therapy
Level of Evidencet
Comments
3 months for first episode
Strong More prolonged or lifetime anticoagulation may be required for recurrences or ongoing risk factors 3 months for first episode Weak If anticoagulation is contraindicated, patients with isolated calf DVT may be monitored with serial noninvasive studies for proximal extension of clot Lifetime Weak Lifetime
Weak
Lifetime Until euthyroid state and sinus rhythm restored for 2-4 weeks
Weak Weak
Lifetime
Weak
Because of limited data, decision to anticoagulate these patients must be carefully individualized; consider anticoagulation in presence of heart failure and in younger patients at low risk of hemorrhage
Lifetime
Weak
3 weeks before and 2-4 weeks after cardioversion
Weak
Only lone AF patients older than 60 have increased stroke risk; consider anticoagulation only if low risk of hemorrhage Anticoagulation not required for cardioversion of other atrial arrhythmias
Lifetime
Weak
Lifetime
Weak
Lifetime
Weak
Lifetime
Weak
Lifetime Lifetime
Weak Weak
For first 3 months qftpr rpnlir^pmpnt IluUI IUI I., M Lifetime
Strong
For 3 months after acute Ml For 3 months after acute Ml
Strong Indications for anticoagulation beyond 3 months
Lifetime Lifetime
Weak Weak
Lifetime
Weak
Anticoagulation not required for uncomplicated mitral valve prolapse or for isolated aortic valve disease or aortic bioprosthetic heart valves in presence of sinus rhythm; adding dipyridamole is optional for patients with mechanical prostheses but is indicated if systemic embolism recurs
despite adequate warfarin therapy
Weak
are uncertain
Weak
After 1 year of therapy at PT ratio of 1.5-2.0, warfarin intensity can be reduced to a PT ratio of 1.3-1.5, if there have been no other recurrences
*Modified from American College of Chest Physicians and National Heart, Lung, and Blood Institute recommendations.8 tstrong=supporting evidence from randomized trials, weak=suggestive evidence from nonrandomized trials or uncontrolled case studies.
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Venous Thromboembolism Deep vein thrombosis andpulmonary embolism. Without a course of long-term anticoagulation following inpatient heparin therapy, the recurrence rate of proximal deep venous thrombosis (DVT) (popliteal vein and above) over the next three months is nearly 50 %, as compared with 2 % to 4 % in therapeutically anticoagulated patients.23 In one randomized trial, a three-month course of low-intensity warfarin therapy (PT ratio of 1.3 to 1.5) was shown to be as effective as a conventional warfarin regimen (PT ratio of 1.5 to 2.0) in preventing recurrent venous thromboembolism in patients with proximal DVT; the low-intensity regimen, however, was associated with a fourfold lower rate of hemorrhagic complications-S % versus 20%. 19 The subcutaneous administration of heparin every 12 hours in a dose sufficient to prolong the activated partial thromboplastin time to 1.5 times the control value six hours after a dose is as effective and safe for proximal DVT as the low-intensity warfarin regimen, although somewhat more expensive and inconvenient. 17'24 This regimen, sometimes referred to as "adjusteddose" subcutaneous heparin therapy, may be useful for patients with contraindications to warfarin, including pregnancy, warfarin allergy, a history of warfarin-induced skin necrosis, or an inability to have regular monitoring of the prothrombin time ratio. Although definitive trials have not been done, the ACCP-NHLBI panel also recommends lowintensity warfarin therapy for patients with pulmonary embolism. Others suggest more intense anticoagulation to a PT ratio of 1.5 to 1.8 for patients with pulmonary emboli.25(j'587) The optimal duration of anticoagulation for patients with proximal DVT and pulmonary emboli is unknown. The recommendations for treating a first episode vary from to 12 months26'27; some clinicians empirically anticoagulate patients with pulmonary emboli longer than those with deep venous thrombi.25 A recent retrospective analysis of patients with DVT or pulmonary emboli28 and one randomized trial of patients with DVT29 did not find higher rates of recurrent venous thromboembolism in patients anticoagulated four to six weeks as compared with patients treated as long as six months or more. A large randomized trial comparing one month and three months of anticoagulation is currently underway in the United Kingdom.27 Pending further studies, the ACCP-NHLBI panel recommends that patients with DVT and those with pulmonary emboli with either no or transient risk factors for venous thromboembolism-such as the postoperative state, immobilization, previous estrogen therapy-receive three months of anticoagulation following a first episode. Patients with permanent risk factors, particularly malignant tumors and hereditary hypercoagulable states, should generally receive lifetime anticoagulation. Following the cessation of anticoagulation for a first episode of venous thromboembolism, the one-year recurrence rate is between 4% and 12% .26 Unfortunately, patients at high risk for recurrence cannot yet be prospectively identified. How long to anticoagulate patients with recurrent venous thromboembolism is also uncertain, although their risk for yet another recurrence following three months of therapy may be 20 % or greater.30'31 For patients with recurrent venous thromboembolism but no other apparent risk factors, some clinical experts recommend anticoagulation for one year for a first recurrence and lifetime anticoagulation for any subsequent recurrences.30 Another group that recommends anticoagulation for one month for an initial episode suggests
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three months of therapy for the first recurrence and lifelong treatment of repeated episodes.27 The management of isolated calf DVT is controversial.26"3233 With this disorder, pulmonary emboli, and especially fatal pulmonary embolism, are much less common than with proximal deep venous thrombi but do occur in a small but uncertain fraction of patients.3234 Untreated, 20% to 30% of cases of calf DVT extend proximally, usually during the first week after the onset of symptoms, increasing the risk of pulmonary emboli and chronic venous insufficiency.26 In a study of patients with venographically confirmed calf DVT, failure to provide at least a six-week course of anticoagulation following intravenous heparin therapy resulted in a 30% recurrence rate of venous thromboembolism, including proximal DVT and pulmonary emboli.35 These results contrast with two recent prospective trials of nearly 1,000 patients with clinically suspected DVT evaluated with serial impedance plethysmography.36'3' Optimally done, this procedure can detect proximal DVT with greater than 90% sensitivity and specificity.38 In these two studies, when initial impedance plethysmography and serial follow-up impedance plethysmography on days 2, 5, and 10 showed no evidence of clot extension into proximal veins, it proved safe to withhold anticoagulant therapy. Based on these considerations, either therapeutic strategy may be applied to patients with calf deep venous thrombi.26'32'33 If, however, serial impedance plethysmography or an accurate alternative noninvasive diagnostic test such as real-time Bmode ultrasonography39 is either unavailable or not of locally validated accuracy, patients with calf DVT confirmed venographically should receive intravenous heparin for seven days followed by low-intensity warfarin or adjusted-dose subcutaneous heparin for three months.8
Atrial Fibrillation About 15 % of all ischemic strokes and 36% of ischemic strokes in persons older than 80 are associated with atrial fibrillation.40 4 Some 2% to 5% of persons older than 65 have atrial fibrillation, and their lifetime risk of stroke is estimated at 35 %40; 50% of these strokes result in disability or death.42(p120) The fraction of these strokes due to cardioembolism, as opposed to coexisting cerebrovascular disease, is unknown. Estimates range from 19% to 80%, but most recent estimates are from 50% to 70% .40'43 The risk of stroke appears to vary among different clinical subgroups of patients with atrial fibrillation (Table 3).4° The highest annual risk is in those patients with either a previous clinical stroke or rheumatic valvular disease, particularly mitral stenosis. Patients with atrial fibrillation who have nonvalvular heart disease due to cardiomyopathy, coronary artery disease, hypertension, thyrotoxicosis, or congenital abnormalities have an intermediate risk of stroke, especially if there is substantial concurrent left ventricular dysfunction.40'4446 Patients younger than 60 with nonvalvular heart disease and paroxysmal atrial fibrillation and patients older than 60 with idiopathic atrial fibrillation without associated heart disease ("lone atrial fibrillation") also have an intermediate risk of stroke.40 In contrast, patients younger than 60 with lone atrial fibrillation appear to be at a low risk for stroke.40'48 The role of other possible risk factors for stroke in these patients (see Table 3) has not yet been adequately delineated.40 The benefit:risk ratio for anticoagulation in each of the
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TABLE 3.-Estimated Annual Stroke Risk in Subgroups of Patients With Atrial Fibrillation (AF)* Degree of Risk
Annual Stroke Risk, 96
High Risk Prio stroke . ............................ Rheumatc mitral valvular disease ...... ......... Internediate Risk Nonvalvular heart disease with left ventricular dysfunction ............................ ......... Paroxysmal AF, younger than 60 ...... Lone AF, older than 60 ........ .............. Low Risk Lone AF, younger than 60 ....... ............. Uncertain Risk Recent-onset versus chronic AF Paroxysmal versus chronic AF, older than 60 Variation in risk according to cause of AF Associated carotid artery disease Previous asymptomatic stroke on computed tomography Echocardiographic features Left atrial size Ventrcular function Mitral regurgitation Left atrial thrombi Other
10-20 4-6 2-5 2.5 2-3
