CHAPTER 132 ORAL ANTICOAGULATION
CHAPTER 132 ORAL ANTICOAGULATION
Vitamin K Antagonists
Chemistry and Mode of Action
Complications of Therapy
Novel Vitamin K Antagonists
Other Oral Anticoagulants
Inhibitors of Coagulation Factor XA
Inhibitors of Thrombin
The original and principal oral anticoagulants—the vitamin K antagonists—have well-known chemistry and pharmacokinetics. The standardized calibration system for monitoring treatment with vitamin K antagonists, the international normalized ratio (INR), is widely accepted. Its use increases the reliability of comparisons of treatment intensity between laboratories and improves interpretation of results obtained in clinical trials. Portable instruments for measurement of the prothrombin time permit self-management in selected cases. Computerized decision support of drug dosing contributes to improved efficacy and safety. The large number of interactions of vitamin K antagonists with other drugs is a major problem during treatment and is often the cause of bleeding complications. Predictors for hemorrhage have been related to characteristics of the patient and underlying disease as well as treatment and hemostatic variables. The detection of mutations and polymorphisms has provided some explanations for resistance or hypersensitivity to vitamin K antagonists. Among the nonhemorrhagic complications are skin necrosis, purple toe syndrome, allergic dermatologic manifestations, hepatic dysfunction, possibly reduced bone mineral density, and teratogenicity. During the perioperative state, treatment with vitamin K antagonists is managed in various ways, depending on the nature of the surgical procedure and the condition that necessitates anticoagulation. For the main indications of treatment—artificial heart valves, nonvalvular atrial fibrillation, myocardial infarction, and venous thromboembolism—large clinical trials have documented the optimum intensity of treatment. For venous thromboembolism, the duration of treatment should be tailored individually according to characteristics of the thrombotic event and presence of prothrombotic risk factors. Minidose warfarin (1 mg/day) is effective in the prophylaxis against thrombosis in central venous catheters, major gynecologic surgery, and metastatic breast cancer. A number of new oral anticoagulants, such as glycosaminoglycans or direct and selective inhibitors of factor Xa or thrombin, are under development and may prove to be safer than vitamin K antagonists due to fewer interactions with other drugs.
Acronyms and abbreviations that appear in this chapter include: INR, international normalized ratio; ISI, international sensitivity index; LMWH, low-molecular-weight heparin; P&P, prothrombin and proconvertin; PT, prothrombin time; rTF, recombinant tissue factor; TURP, transurethral resection of the prostate.
A hemorrhagic disease in cattle caused by moldy sweet clover hay was described in 1922.1 The absence or delay of blood clotting was correlated to a greatly diminished quantity of prothrombin. Isolation and purification of the “hemorrhagic agent” confirmed that the substance was dicumarol, 3,3-methylene-bis-[4-hydroxycoumarin],2 which was promptly made available for clinical studies. The first experiences of the prophylactic and therapeutic effects of the drug in deep vein thrombosis, as well as its hemorrhagic complications, were published in 1942.3,4 and 5 Warfarin, an acronym for the Wisconsin Alumni Research Foundation, in recognition of its synthesis at the University of Wisconsin in 1948, or 3-(1-phenyl-3-oxobutyl)4-hydroxycoumarin, is now the most commonly used coumarin derivative worldwide. The available compounds in different countries are either coumarin derivatives or indanedione derivatives. Some of the substances are also used as rodenticides.
These drugs have traditionally been termed oral anticoagulants, but are referred to as vitamin K antagonists in this chapter to highlight their specific effect and to distinguish them from new oral anticoagulants that have other mechanisms of action.
VITAMIN K ANTAGONISTS
CHEMISTRY AND MODE OF ACTION
The coumarin derivatives have in common a 4-hydroxy–coumarin nucleus with a substituent in the 3 position (Fig. 132-1). All the 4-hydroxy–coumarin compounds have an asymmetric carbon atom, and the clinically available warfarin preparations consist of a racemic mixture of the S and R enantiomers. (S)-warfarin is four to five times more potent than (R)-warfarin as an anticoagulant and is more susceptible to interactions with other drugs.6 The formulation of warfarin for oral administration is in a crystalline form. However, amorphous warfarin sodium, which was temporarily produced, did not turn out to be bioequivalent,7 and this may also be the case for some of the generic warfarin formulations.8
FIGURE 132-1 Structure of warfarin sodium and phenindione. Common structures for coumarin and indanedione derivatives appear in boldface.
The vitamin K–dependent coagulation factors II, VII, IX, and X undergo posttranslational g-carboxylation of approximately 10 glutamic acid residues in the N-terminal Gla domain9,10 and 11 (see Chap. 112). This modification is required for the ability of the coagulation factors to bind calcium and to localize the enzymatic processes in which they participate to a phospholipid surface, such as activated platelet membranes. A reduction of the g-carboxylated sites by 1 to 6 residues will progressively impair the coagulation activity from 70 percent of normal to no activity at all. With therapeutic doses of warfarin, approximately 3 of 10 glutamic acid residues in prothrombin are not carboxylated.12,13 and 14
Simultaneously with g-carboxylation, vitamin KH2 is converted to vitamin K epoxide, which is converted back to KH2 by the sequential actions of vitamin K epoxide reductase and vitamin K reductase. These two enzymes are inhibited by the coumarin derivatives, thereby precluding further g-carboxylation.15,16 The coagulation inhibitors protein C and protein S, as well as osteocalcin, also undergo posttranslational g-carboxylation, and vitamin K antagonists cause the synthesis of their hypo- and acarboxylated forms. Some of the drug-related adverse effects can be explained by the reduced activity of these proteins (see “Skin Necrosis” and “Teratogenicity” under “Complications of Therapy”).
Warfarin is highly water soluble and is absorbed rapidly and completely from the stomach and upper gastrointestinal tract, reaching peak concentrations in plasma 60 to 90 min after oral ingestion. Impaired absorption has been described in a case with resistance to warfarin and dicumarol but not to an indanedione derivative.17 In the circulation, 98 to 99 percent of warfarin is bound to proteins, primarily to albumin, and therefore only a small fraction of the drug is biologically active. The binding to albumin occurs at site I, which is shared with phenylbutazone and azapropazone.18 Displacement of warfarin from albumin increases its anticoagulant activity, but at the same time the rate of elimination of the drug increases. Warfarin accumulates rapidly in the liver, mainly in the microsomes.19
Metabolism of warfarin is different for the two enantiomers. The biologically more potent (S)-warfarin is hydroxylated by cytochrome P450 2C9 (CYP2C9) to 7-hydroxywarfarin. Mutations in the CYP2C9 gene result in three allelic variants, and a patient with very high sensitivity to warfarin was demonstrated to be homozygous for CYP2C9*3.20 (R)-warfarin is metabolized by CYP1A2 to 6- and 8-hydroxywarfarin. The hydroxycoumarins are excreted by the kidneys. The elimination half-life of warfarin is 35 to 45 h, and the pharmacokinetics appear to be dose dependent.21 Warfarin may also be administered intravenously, and inadvertent percutaneous absorption of a warfarin-type rat poison has been reported to cause bleeding complications.22
The other vitamin K antagonists have similar pharmacokinetic characteristics, except for differences in elimination.23 Dicumarol has a lower degree of absorption from the gastrointestinal tract, and up to 36 percent of the drug can be retrieved inert in the stool.24
The variability in warfarin dose requirements to achieve a given extent of anticoagulation is wide, ranging from about 1 to 20 mg/day. This may be due to differences in clearance of the drug by the liver and in target-organ sensitivity. There is a significant negative correlation between age at start of therapy and dosage, with a reduction of requirements of approximately 20 percent over a 15-year period.25 The explanation for this finding is at least partly the decline in hepatic mass with age.26 In children, there is an even more pronounced reduction of warfarin requirements with age, with mean doses of 0.32 and 0.09 mg/kg/day in those under 1 year of age and 11 to 18 years of age, respectively.27 A number of algorithms and nomograms have been constructed to aid the physician in predicting the maintenance dose. They are usually based on the level of anticoagulation achieved after 2 to 4 days on a repeated loading dose.28,29
In rare cases, exceptionally high doses are required to achieve anticoagulation. The first hereditary form of resistance to coumarin, as well as to phenindione, with an autosomal dominant pattern was described in 1964.30 Mechanisms of warfarin resistance include impaired absorption,17 high clearance of (S)-warfarin,31 or decreased affinity of warfarin for the receptor,32 presumably associated with a decreased sensitivity of epoxide reductase.33 However, poor compliance, interactions with food or drugs, laboratory errors, or pharmacokinetic changes always have to be excluded.
INITIATION OF THERAPY
Vitamin K antagonists should be started concomitantly with heparin treatment34 since it takes several days for the vitamin K antagonists to achieve an antithrombotic effect.35 Factor VII concentration drops rapidly, reaching levels that produce a prolonged prothrombin time within 24 h, but the other vitamin K–dependent coagulation factors have longer half-lives, and an antithrombotic effect is not achieved until after 72 to 96 h.36 Initiation of warfarin therapy within 3 days compared to after 7 days,37 or on day 1 compared to day 5,38 provides the same benefit with equal safety, and thus the current recommendation is to start warfarin on day 1.
The “loading” doses of warfarin that were used in the past frequently caused hemorrhage and have been abandoned.39 The plasma levels of inhibitor protein C decrease much faster than the levels of factor X when warfarin is initiated at a dose of 8 mg twice a day for 2 to 3 days instead of 6 mg daily for 3 days, and it has been speculated that the higher dose produces a transient hypercoagulable state.40 However, in a study comparing initiation of 15 mg warfarin on day 1 and 7.5 mg on days 2 and 3 with a regimen of 15 mg/day until the INR reached 1.87, both regimens were found to be safe and effective, and heparin treatment could be discontinued after 6 and 5 days, respectively.41
In patients with inherited deficiency of protein C or protein S, the initiation of treatment with vitamin K antagonists should be done with small doses and prolonged overlap with heparin to avoid skin necrosis (see “Skin Necrosis,” “Complications of Therapy”). For patients with protein C deficiency, treatment with warfarin and protein C concentrate42 or fresh-frozen plasma might be considered.
DISCONTINUATION OF WARFARIN
The optimal mode of cessation has likewise been a subject of debate. Indeed, there is a transient elevation of thrombin-antithrombin complexes and prothrombin fragment F1+2 after discontinuation of warfarin treatment for venous thromboembolism, with more pronounced changes after abrupt than after gradual discontinuation.43 It has, however, been difficult to prove the clinical disadvantage of abrupt cessation in patients with venous thromboembolism. In patients treated with warfarin after thrombolysis for myocardial infarction, abrupt cessation of warfarin created a gap between the rapidly rising levels of factors VII and IX and a slow normalization of protein C and S levels, mirrored by a hypercoagulable state associated with some thromboembolic events and increased levels of fibrinopeptide A.44
Anticoagulant treatment is monitored by a one-stage prothrombin time (PT) test, the Quick thromboplastin time,45 or a modification thereof, the prothrombin and proconvertin (P&P) method.46 A thromboplastin extract of a tissue, providing both tissue factor and phospholipids, is added to citrated plasma, and then the plasma is recalcified to initiate the reaction. The coagulation time reflects the activity of the extrinsic and common pathway of the coagulation cascade. In the P&P method, adsorbed ox plasma as a source of factor V and fibrinogen is also added, and thus the plasma level of these factors will not have any influence on the result.
Due to wide variations in the sensitivities of the thromboplastins used and in the recommendations for therapeutic ranges, patients in different countries or even at different centers within a single country received substantially different intensities of anticoagulation.47 As a result, multicenter trials and comparisons of treatment effects were impossible to perform or to interpret. For these reasons, recommendations were issued in 1985 to standardize the reporting of the PT by using the INR.48 This is a calibration system based on a linear relationship between the logarithm of PT ratios obtained with the reference and test thromboplastins. For an individual test, the INR is calculated according to the formula INR = (PTPatient / PTControl)ISI, where the international sensitivity index (ISI) is a correction factor for the responsiveness of the thromboplastin to the reductions in the vitamin K–dependent coagulation factors. The precision of the INR increases with lower ISI values,49 and hence it is important that the latter are as low as possible or, more specifically, close to 1.0, which is the ISI value of the World Health Organization international reference preparation. However, the type of instrument used will also affect the ISI value,50 and indeed, each local reagent-instrument combination needs calibration for the achievement of reliable INR values.51 The citrate concentration in the test tubes also affects the INR, and a single concentration should therefore be used.52 Since pooled plasma from patients stabilized on warfarin is used for the INR model, it could be presumed that INR values obtained during the induction phase are unreliable, but in a series of 43 patients tested during the initial 5 days with five different thromboplastins, the INR system showed less variance than did the PT ratios.53 The system is widely accepted in Europe and the United States.
Due to the risk of viral contamination with tissue factor extracted from animal tissues, recombinant human tissue factor (rTF)54,55 is the preferred reagent for monitoring treatment with vitamin K antagonists.56,57 The presence of heparin in the patient’s sample may influence the INR values, but some reagents, including the one based on rTF, are unaffected by heparin concentrations up to 1 IU/ml.58 Similarly, the presence of a lupus anticoagulant may have a pronounced effect on the test result, leading to falsely high INR values, but this is also to some extent dependent on the sensitivity of the thromboplastin.59,60
Although other assays to monitor treatment have shown promising results,61,62 and 63 none has replaced thromboplastin reagents. Assays of prothrombin fragment 1+2 and thrombin-antithrombin complexes have also been proposed for monitoring, but have not demonstrated improved ability to predict treatment failure or hemorrhagic risk.64,65
Portable instruments suitable for home use produce assay values that correlate well with results produced by laboratory instruments.66 Training patients in capillary blood sampling and warfarin dose adjustments can permit self-management with vitamin K antagonists.67,68 This method may also be advantageous for families with children requiring anticoagulant treatment.69
COMPUTERIZED DECISION SUPPORT
Anticoagulant therapy is often suboptimal in routine practice, with a high percentage of test results outside the targeted range.70 A computerized decision support system used by physicians and nurses can improve the quality of treatment.71,72 By collection of data via the computer system, quality control of the safety and efficacy of the anticoagulation is also facilitated. In a randomized study, computer-based control resulted in a significantly lower number of altered doses.73
ORGANIZATION OF ANTICOAGULANT MONITORING
The Netherlands has a nationwide organization for control of treatment with vitamin K antagonists and has documented that 80 percent of the PT of patients on long-term treatment were within the target range.74 Centralization of patients to specialized anticoagulation clinics is likely to offer an improvement of the anticoagulant management, with a reduction of thromboembolic events, major hemorrhages, and costs of hospitalizations, as demonstrated by an overview,75 a study of two consecutive cohorts,76 and a small randomized trial.77
PROBLEMS DURING MONITORING
Unstable INRs may be due to problems with reagents, instruments, or staff. Inexperienced monitors may not wait long enough for the development of a new steady state after dose adjustments and then overshoot the desired INR. Even minor matters may affect the results. Thus, the hour of the day when the blood sample is obtained may be important, since there is a diurnal variation of the INR in patients treated with vitamin K antagonists, with the peak between 4:00 A.M. and 8:00 A.M. and the nadir between 6:00 P.M. and midnight.78 The main uncertainty is, however, caused by the numerous interactions with vitamin K antagonists, described in the following section. It is therefore not surprising that the instability of anticoagulation increases with the number of concomitant drugs taken, irrespective of known specific interactions.79
Vitamin K1 (phylloquinone) is the predominant form of vitamin K present in the diet. Intake of vitamin K may cause a competition with the effect of the 4-hydroxycoumarins. Lists of foods and their vitamin K content are available from some of the manufacturers of vitamin K antagonists, but there is probably little benefit in supplying them to patients without a detailed explanation, especially since some patients may respond by omitting all vegetables from their diet. In fact, relatively few interactions between vitamin K antagonists and foods are clinically relevant, although the warfarin antagonism produced by large amounts of avocado80 or broccoli81 is highly probable. In the case of avocado, the vitamin K content is not high, but avocado oils seem to interfere with warfarin in some other way. Balanced advice to patients is the following82,83
Avoid major changes in the diet. If a change is indispensable, consult the physician and increase the frequency of monitoring temporarily.
Avoid avocado, kale, and parsley, except as a garnish or minor ingredient, as well as the Japanese dish natto.
Choose up to one serving (100 g) per day from the following: broccoli, brussels sprouts, spinach, turnip greens, or other greens.
Discuss with the physician any substantial increase or decrease in the intake of lentils, garbanzo beans, soybeans, soybean oil, liver, or other sources rich in vitamin K.
Alcohol intake, other than the occasional drink, should be discouraged.
Supplements of vitamin E seem to cause interference with vitamin K and should be avoided. Supplements with vitamin A and C have occasionally caused an increase or decrease, respectively, of the PT, and doses higher than the recommended daily allowances should be avoided.82
For poorly controlled anticoagulated patients, where no drug interaction or other obvious reason can be identified, a diet with a constant vitamin K1 content may be beneficial.84,85
Poor absorption of the vitamin K antagonists may occur in patients during periods with diarrhea, with use of liquid paraffin laxatives,86 and in patients with malabsorption syndrome.
There is an ever-growing list of drug interactions with vitamin K antagonists (Table 132-1 and Table 132-2). The vast majority of those have been reported in patients treated with warfarin, but in many cases they have been described also with at least one of the other vitamin K antagonists. At high doses, the nonsteroidal anti-inflammatory agents, as well as acetylsalicylic acid, may cause hypoprothrombinemia through inhibition of hepatic metabolism via CYP450 2C9 (phenylbutazone and analogs) or protein-binding displacement.87 Furthermore, these drugs increase the risk of bleeding by inhibiting platelet function. Finally, the risk of upper gastrointestinal hemorrhage is increased by the ulcerogenic effect of these agents.88
TABLE 132-1 REPORTED DRUG INTERACTIONS WITH WARFARIN AND OTHER VITAMIN K ANTAGONISTS CAUSING INCREASED ANTICOAGULANT RESPONSE
TABLE 132-2 REPORTED DRUG INTERACTIONS WITH WARFARIN AND OTHER VITAMIN K ANTAGONISTS CAUSING DECREASED ANTICOAGULANT RESPONSE
A number of different mechanisms of drug interactions with vitamin K antagonists have been described (Table 132-3). In most cases, metabolism of warfarin is inhibited, which in turn can be stereoselective for either the R- or S-enantiomer.83
TABLE 132-3 MECHANISMS FOR DRUG INTERACTIONS WITH VITAMIN K ANTAGONISTS
Amitriptyline causes an unusual type of interaction with phenprocoumon during which great fluctuations of the PT have been observed.89 Chinese herbs and traditional medicines have been reported to exert an inhibiting effect on the metabolism of warfarin, sometimes resulting in pronounced hyperanticoagulation.90,91 and 92
An accentuated effect of vitamin K antagonists during the summer has been reported as a result of exposure to insecticides, such as ivermectin or metidation.93,94
COMPLICATIONS OF THERAPY
Incidence Vitamin K antagonists cause more fatal side effects than any other drug in absolute numbers.95 Virtually all fatalities are related to bleeding complications. The incidence of this complication varies from one study to another due to differences in intensity of anticoagulation and patient populations. In a survey of seven trials in venous thromboembolism, only one fatal hemorrhage among 1283 patients anticoagulated for 3 months was identified,96 which illustrates the low risk observed in studies with a selected patient population. Table 132-4 compares the incidence of fatal hemorrhage in other large studies.
TABLE 132-4 INCIDENCE OF FATAL HEMORRHAGE IN VARIOUS PATIENT POPULATIONS
The definitions of major hemorrhages vary among studies. Some have specifically defined “life-threatening” hemorrhages, which had an incidence of 0.89 per 100 patient-years in a cohort study97 and 0.83 in a combined cross-sectional and prospective cohort study,98 with 7500 combined patient-years of observation. Major hemorrhages may include those with a certain drop in hemoglobin but without hospitalization, and the incidence per 100 patient-years ranged between 1.7 and 2.1 in four studies of patients with atrial fibrillation, between 0.8 and 4.1 in four trials on patients with prosthetic heart valves,96 and between 2.2 and 7.8 in three trials on patients with venous thromboembolism, with at least 100 patient-years of follow-up.99,100 and 101 In cohort studies, the incidence of major hemorrhages ranges from 1.2102 to 7.097 per 100 patient-years.
Locations The gastrointestinal tract is the most common site for major hemorrhages (66%),98 and the site of bleeding, usually a peptic ulcer, can be precisely identified in 83 percent of cases.103 However, large-bowel malignancy is another common organic lesion found in these cases, which emphasizes the importance of performing a thorough investigation to locate the source of bleeding.104 Acute abdomen requiring laparotomy in anticoagulated patients is typically caused by intramural intestinal hematoma.105
Intracranial bleeding was the most common cause of fatal hemorrhage,106 with a mortality rate of 77 percent in a prospective study of patients admitted to a department of neurosurgery.107 A majority of these patients had intracerebral hemorrhage, whereas a minority had subdural hematoma; the latter was associated with a better prognosis.107,108 Predictors for a poor prognosis of intracranial hemorrhage are age over 60 years, hematoma in the midline or ventricles, coma, arterial hypertension, and hyperanticoagulation at the time of bleeding.109 The risk of developing an intracranial hematoma after an apparently minor head injury has been estimated to be 10 times higher in patients treated with warfarin.110
Femoral neuropathy after retroperitoneal hemorrhage,111 radial nerve compression neuropathy after routine venipuncture,112 and acute carpal tunnel syndrome due to intraneural hemorrhage in the median nerve113 are rare but serious complications. Unusual sites of hemorrhage include spermatic cord hematoma,114 spontaneous spinal epidural hematoma after a coughing spell,115 and choroidal hemorrhage in age-related macular degeneration.116
Predictors Several predictors for major hemorrhage during treatment with vitamin K antagonists have been identified (Table 132-5). Among these predictors, the influence of age has been controversial. For intracranial hemorrhage, previous ischemic cerebral events, old age, hypertension, and high intensity of anticoagulation were identified as predictors.107,117
TABLE 132-5 PREDICTORS FOR HEMORRHAGIC COMPLICATIONS
Increased plasma levels of tissue plasminogen activator, its inhibitor, von Willebrand factor, and soluble thrombomodulin, all measured by immunochemical methods, have been found to correlate with the risk of hemorrhage.118,119 These could all be markers of endothelial dysfunction and vascular disease.
Two groups have reported the interesting finding of increased bleeding in patients with missense mutations in Ala10 in the propeptide of factor IX.120,121 The mutated protein (Ala10Val in two patients and Ala10Thr in another two) exerted a reduced affinity of the g-glutamylcarboxylase enzyme for the propeptide. This had no effect on plasma factor IX levels in the absence of vitamin K antagonists, but it significantly increased the patients’ sensitivity to warfarin treatment, with factor IX levels dropping to less than 1 to 3 percent of normal, compared to 30 to 40 percent in patients with the wild-type factor IX. Furthermore, polymorphisms in the gene coding for cytochrome P450 CYP2C9, the principal catalytic enzyme for (S)-warfarin, give rise to decreased warfarin requirement and confer an increased risk of major bleeding.122
Treatment In patients with a major hemorrhage, rapid reversal of the anticoagulant effect is essential. It is frequently difficult to give sufficient amounts of fresh-frozen plasma, due to volume restrictions, and some experts recommend infusion of prothrombin-complex concentrates.123 However, these concentrates may increase the risk of thrombosis since they contain activated coagulation factors.
Minor bleeding complications have not received much attention in the literature, but a study on epistaxis during warfarin treatment showed that the medication could be continued safely, provided that the INR was within the therapeutic range and that local hemostatic measures were taken.124
Reversal of Overdose without Hemorrhage In the absence of hemorrhage, hyperanticoagulation is preferably reversed by either discontinuation and careful observation or by vitamin K1 (phytonadione) administration. An intravenous dose of 0.5 mg vitamin K1 seems sufficient to achieve an INR in the therapeutic range in most patients within 24 h.125 However, this route of administration should be avoided if possible, since anaphylactic reactions have been described.126 For subcutaneous administration, an average dose of 4.9 mg vitamin K1 was reported as necessary,127 whereas by the oral route, between 1 and 2.5 mg were found effective and safe, reaching a therapeutic level after 16 h.128,129 and 130 Doses of vitamin K1 of 10 mg or more should be avoided, since they lead to warfarin resistance for up to a week.
Skin Necrosis Initially described in 1943,131 skin necrosis occurs with a frequency of about 1 in 5000 patients treated with vitamin K antagonists,132 although there have been occasional reports of a much higher frequency133 (see Chap. 121). It affects predominantly women (85%) and may be related to the distribution of subcutaneous fat. Areas typically involved are breasts, thighs, and buttocks. The onset is usually within 3 to 10 days from initiation of anticoagulation, but a delay of up to 15 years has been reported.133 Skin necrosis does not necessarily reappear with reinstitution of vitamin K antagonists.
Initial symptoms and signs are localized pain with a maculopapular rash, which within 24 to 48 h progresses to hemorrhagic lesions, hemorrhagic bullae, and necrosis, leaving an eschar that heals slowly. Plastic surgery is frequently required,134 and when the breast is affected, mastectomy may be necessary.
It is generally believed that the pathogenic mechanism is a hypercoagulable state caused by an imbalance between severely depressed levels of protein C and protein S and only a mild reduction of coagulation factors II, IX, and X.132,133 Preexisting deficiency of protein C or protein S, or use of large loading doses of warfarin may accentuate this imbalance. A deficiency of antithrombin may also contribute to the pathogenesis.135 Histologically, fibrin deposits are seen in small veins and venules in the dermis and subcutaneous fat, surrounded by hemorrhage and diffuse necrosis.
Prompt administration of vitamin K has been reported to halt the progression to skin necrosis.136 Treatment with vitamin K antagonists should be discontinued immediately in any event and reversed with plasma or, in the case of protein C deficiency, with a concentrate of protein C if available. Anticoagulation is continued with heparin until the lesions have healed, whereafter warfarin may be resumed, starting a low dose of 1 to 2 mg/day and gradually increasing it over 10 to 12 days.133,137
Purple Toe Syndrome Since the first report of six patients with this complication,138 only a few additional cases have been described (see Chap. 121). The syndrome develops 3 to 8 weeks after initiation of anticoagulation,138 usually with bilateral burning pain and dark blue discoloration of the toes and sides of the feet, with blanching of the skin on pressure.133 Occasionally, the hands are involved. Most of the patients have underlying cardiac disorders, diabetes mellitus, or peripheral vascular disease. It is presumed that the mechanism is cholesterol embolization from atherosclerotic plaques. Warfarin may make the plaque more friable by decreasing fibrin deposition or by hemorrhage into the plaque.133 The burning pain, but not the discoloration, disappears on discontinuation of warfarin.133 The safety of restoring warfarin in patients who have developed this complication is unclear.
Other Nonhemorrhagic Side Effects Other dermatologic side effects of warfarin are maculopapular,139 vesicular, or urticarial rashes,140 often very itchy, occurring weeks to months after beginning anticoagulation132 but occasionally after the first dose.140 Eosinophilic pleurisy141 and vasculitis142 have been described in connection with warfarin therapy. Phenindione has also been reported to cause severe hypersensitivity.23
There are a few reports of toxic hepatitis induced by different vitamin K antagonists143,144 and descriptions of intrahepatic jaundice.145,146
Finally, there are contradictory reports regarding the effect of warfarin on bone mineral density. Although osteocalcin is reproducibly reduced during warfarin treatment,147,148 and 149 in combination with increased loss of calcium in urine,147 the literature is inconsistent with regard to the effect of warfarin on reduced bone mineral density148,149,150,151 and 152 and the incidence of fractures.151
The teratogenic effects of vitamin K antagonists consist of midface and nasal hypoplasia, stippled epiphyses, hypoplasia of the digits, optic atrophy, and mental impairment.153 This is summarized as the warfarin embryopathy syndrome, but it can also be induced by other vitamin K antagonists given between weeks 6 and 12 of gestation. Previous estimates of the frequency of the syndrome after exposure to warfarin during weeks 6 to 12 range from 5.4 to 28.6 percent.154,155 In more recent retrospective and prospective studies, 0 of 46156 and 1 of 11157 first-trimester exposures respectively resulted in embryopathy, whereas in a retrospective study of Chinese patients, 16 of 29 children had features of embryopathy, which in almost all of them was restricted to nasal hypoplasia.158
A similar syndrome, with nasal hypoplasia, punctate calcifications, and abnormalities of the spine, has been described in children of mothers with vitamin K deficiency due to malabsorption, in patients with epoxide reductase deficiency,159 and in homozygotes for a point mutation in the g-glutamylcarboxylase gene associated with a deficiency of all vitamin K–dependent coagulation factors and inhibitors.160 With the addition of distal phalangeal hypoplasia, a similar constellation is found in X-linked, recessive chondrodysplasia punctata, where the mutations result in a deficiency of a heat-labile arylsulphatase.161
Vitamin K antagonist therapy during any trimester can cause central nervous system hemorrhage in approximately 1 percent of fetuses or central nervous system malformation without apparent hemorrhage in about 4 to 5 percent.154
Artificial Heart Valves and Pregnancy There are numerous reports of artificial heart valve thrombosis during pregnancy, the majority of which occurred during anticoagulation with heparin, and some with fatal outcome.156,157,162 It has therefore been considered advisable to use a vitamin K antagonist for these patients during the second and early phase of the third trimester after providing mothers with information about the risks and benefits in comparison with heparin.154
Warfarin is not contraindicated during breastfeeding, since the concentration in breast milk is less than 25 ng/ml and warfarin is not detectable in the plasma of the breastfed infants.163
One of the frequent questions regarding treatment with vitamin K antagonists concerns the management during surgery or other invasive procedures. The possibilities range from uninterrupted anticoagulation to reversal of the vitamin K antagonism.
There is no need to reduce or discontinue anticoagulant treatment for cutaneous surgery164,165 or for soft-tissue aspirations or injections.166,167 Pacemaker surgery is also safe, provided that proper surgical technique is used.168 For oral surgery, randomized, placebo-controlled studies have shown that unchanged anticoagulation is safe, provided that it is combined with local irrigation or a mouth rinse with a 5% solution of tranexamic acid in connection with surgery and then repeated four times daily for a week.169,170 and 171 However, it has also been demonstrated that discontinuation of treatment with vitamin K antagonists for 2 days prior to the tooth extraction to achieve an INR of 1.5 or less may be as safe, even in patients with artificial heart valves.172 Local anesthesia of the lower jaw with a posterior nerve block should probably be avoided.
Treatment of benign prostate hyperplasia with neodymium:YAG laser ablation has been performed without interruption of the anticoagulation, but there is a risk of major hemorrhage of approximately 15 percent.173,174
For cardiac surgery, treatment with vitamin K antagonists can be continued, maintaining an INR of about 2.4.175 In comparison with a reduced dose of warfarin, this regimen led to a lower heparin requirement to prolong the activated coagulation time and diminished blood loss.175 For vascular surgery, surgeons must use meticulous hemostatic technique to allow uninterrrupted anticoagulation for prevention of occlusion of graft or operated blood vessel.
For other types of surgery, a modification of the treatment is necessary. Thus, it is useful to know the rate by which the INR decreases after discontinuation of warfarin. The results of a kinetic study in 22 patients are presented in Table 132-6. The exponential decay of INR does not start until 29 h after the last dose.176 In case of anticoagulation after venous thromboembolism, the likelihood of a perioperative thromboembolic event during a few days is smaller than the risk of postoperative hemorrhage, and thus, brief discontinuation of warfarin is safe close to the time of planned surgery.177 However, if thrombosis occurred close to the time of planned surgery, it is preferable to postpone surgery or to follow one of the regimens suggested for patients with artificial heart valves. In the latter patients, the risk of thrombus formation on the valve may be perceived as low during a few days of interrupted anticoagulation, since the annual risk without any antithrombotic treatment averages about 10 percent.178 This does not take into account the increased perioperative risk due to activation of coagulation and of the fibrinolytic activity. Thus, in one study, 2 of 10 patients with mitral or combined mechanical valves had fatal strokes when anticoagulation was interrupted 3 to 5 days before surgery.179
TABLE 132-6 DECREASE IN THE MEAN INR (±SD) AFTER DISCONTINUATION OF WARFARIN
A regimen that has been used for elective surgery in 197 anticoagulated patients180 is shown in Fig. 132-2. Of 84 patients with artificial heart valves, major hemorrhage occurred in 3 who had transurethral resection of the prostate (TURP) and in 8 of 99 with major surgery, whereas 2 of the 197 patients developed ischemic stroke.180 TURP is a procedure with a high hemorrhagic risk, and in another study, a similar regimen, but with complete interruption of heparin 4 h before and throughout surgery, was attempted.181 Still, 1 of 12 patients had hemorrhage requiring transfusion, and 3 were readmitted for late bleeding. In general, the hemorrhagic complications have required transfusion or reoperation, whereas the ischemic strokes have resulted in chronic sequelae.
FIGURE 132-2 Example of a perioperative regimen for patients on anticoagulant therapy with a high risk of thromboembolism. The infusion rate of heparin is increased to 210 U/h when the patient returns to the ward. Heparin is discontinued when the INR is in the therapeutic range for 2 consecutive days. (Adapted from S Vigano’D’Angelo et al.180).
MECHANICAL HEART VALVES
The risk of thromboembolism depends on the type and position of the prosthesis and, to some extent, on patient-related factors. In a randomized study, the risk was lower with Björk-Shiley valves than with Edwards-Duro-Medics or Medtronic-Hall valves.182 In a meta-analysis, the risk of thromboembolism was highest with a caged-ball valve (Starr-Edwards), 30 percent lower with a tilting disk valve (Björk-Shiley, Sorin, Medtronic-Hall, and Omnicarbon), and 50 percent lower with a bileaflet valve (St. Jude, DuroMedics, and CarboMedics).178 In a cohort study, the risks with these different valves per 100 patient-years were 2.5, 0.7, and 0.5, respectively.183 The risk is twice as high with a mitral prosthesis as with an aortic prosthesis.178 Other factors that may increase the risk of thromboembolism are age,183 hypertension, and smoking,184 whereas the effects of left atrial enlargement and atrial fibrillation have been controversial.184,185
A retrospective cohort study of 1608 unselected patients with mechanical heart valves showed that the optimal antithrombotic effect was achieved at an INR of 2.5 to 4.9, and thus a target of 3.0 to 4.0 was recommended.183 In one study, a target INR of 2.0 to 3.0 was as effective as an INR of 3.0 to 4.5, but there were significantly fewer minor hemorrhages in the former group.186 The risks of thromboembolism were, however, 2.4 and 2.1 per 100 patient-years, respectively, compared to 0.71 in the cohort study; thus, whether the intensity can be lowered is controversial.
Several studies have been performed with the St. Jude Medical prosthesis with low-intensity warfarin prophylaxis (INR £ 2.5) in combination with dipyridamole and sometimes also acetylsalicylic acid. The incidence of thromboembolism ranged from 0.5 to 1.3 per 100 patient-years.187,188,189 and 190 In a meta-analysis of five randomized trials where antiplatelet therapy or placebo was added to the prophylaxis with vitamin K antagonists, the combined regimen reduced thromboembolism by 67 percent, but at a cost of a 65 percent increase in hemorrhage and 250 percent increase in major gastrointestinal hemorrhage.191 In a review of 16 studies with warfarin and acetylsalicylic acid compared with monotherapy with either agent, it was concluded that the combination should be reserved for patients with a high risk of thromboembolism and possibly also for those with ischemic heart disease, and that the daily dose of acetylsalicylic acid should not exceed 100 mg.192
Bioprosthetic heart valves also confer a risk of thromboembolism, accentuated during the first 3 months after surgery. During this period, it is recommended to use vitamin K antagonists, aiming at an INR 2.0 to 3.0, and to continue warfarin indefinitely in cases with atrial fibrillation, atrial thrombosis detected at echocardiography, or after a systemic embolic episode.193
NONVALVULAR ATRIAL FIBRILLATION
To reduce the incidence of ischemic stroke of 4.5 percent per year in chronic nonvalvular (nonrheumatic) atrial fibrillation,194 prophylaxis is considered increasingly important. Five major placebo-controlled trials have been performed to evaluate warfarin in the primary prevention of thromboembolism (Table 132-7). A meta-analysis of these trials, including 3706 patients, showed a reduction of relative risk of ischemic stroke of 68 percent with warfarin, valid for all age groups except in those younger than 65 years of age.195 The annual incidence of fatal bleeding ranged from 0.0 to 0.8 percent, while the annual incidence of major hemorrhages ranged from 0.2 to 2.0 percent. The recommended target INR is 2.0 to 3.0.194 At this level, warfarin reduces the levels of prothrombin fragment 1+2, b-thromboglobulin, and fibrin D-dimer, which are elevated before treatment. Minidose warfarin does not affect these parameters196,197 and was not shown to be clinically effective.198
TABLE 132-7 EFFECT OF WARFARIN COMPARED TO PLACEBO IN THE PRIMARY PREVENTION OF ISCHEMIC STROKE DUE TO NONVALVULAR ATRIAL FIBRILLATION
Serial transesophageal echocardiography in 14 patients with atrial fibrillation demonstrated that during 4 weeks of anticoagulation with warfarin 16 of 18 atrial thrombi resolved completely and no new thrombi were formed.199 This is in line with the experience that the use of warfarin for 3 to 4 weeks before cardioversion reduces the 1 to 3 percent incidence of procedure-related thromboembolism by 90 percent.200 There is a potential for thrombus formation in the atria during the weeks after successful cardioversion due to stunning of mechanical function and decreased left atrial appendage emptying velocity.201 Anticoagulation should therefore be provided for 3 weeks prior to and 4 weeks after cardioversion at an intensity of INR 2.0 to 3.0 or, alternatively, with heparin.202,203
SECONDARY PROPHYLAXIS AFTER CEREBRAL ISCHEMIA
In a randomized trial in patients with cerebral ischemia of presumed arterial, noncardiac origin, secondary prophylaxis with warfarin targeted at an INR of 3.0 to 4.5 was not safe and resulted in 3.0 fatal and 4.8 intracranial hemorrhages per 100 patient-years. Moreover, this regimen was not more effective than acetylsalicylic acid, 30 mg/day.204 In a small, nonrandomized study, patients with systemic embolization and mobile aortic atheroma had a reduced risk of stroke if they received warfarin.205 In patients with nonvalvular atrial fibrillation, secondary stroke prevention with warfarin (target INR 2.5 to 4.0) reduced the risk of stroke from 12 to 4 percent per year without causing any intracranial bleeding event, whereas acetylsalicylic acid, 300 mg/day, was not more effective than placebo.206 In comparison with indobufen 100 or 200 mg b.i.d., warfarin targeted at an INR of 2.0 to 3.5 was equally effective in preventing vascular complications.207
ISCHEMIC HEART DISEASE
Primary prevention of thrombosis in patients at high risk of ischemic heart disease is effective using the combination of a low dose of warfarin and acetylsalicylic acid.208 Thus, warfarin targeted at an INR of 1.3 to 1.8 reduced the risk of myocardial ischemic events, and addition of low-dose acetylsalicylic acid conferred an additional benefit, although the risk of bleeding increased.208
In patients with unstable angina, the addition of warfarin, targeted at an INR of 2.0 to 2.5, to acetylsalicylic acid 150 mg/day reduces the risk of progression of the culprit lesion.209 However, after aortocoronary bypass surgery, warfarin, targeted at an INR of 2.8 to 4.8, did not reduce the risk of vein graft occlusion in comparison with acetylsalicylic acid 50 mg/day.210 Angiographic follow-up of the patency of vein grafts did not reveal any positive effect of warfarin on the progression of atherosclerosis.211
Patients with myocardial infarction have a 10 percent risk of suffering a reinfarction during the first year, followed by an annual risk of 5 percent.212 Secondary prophylaxis is therefore essential; however, of the many randomized studies performed, only a few were sufficiently large to allow for firm conclusions (Table 132-8). These studies, as well as a meta-analysis,213 demonstrated a reduction of mortality and major cardiovascular events by administration of warfarin. Although there was a significant increase in the risk of major hemorrhage, there was an overall benefit from anticoagulation.213 Data from the largest of these trials (ASPECT) was used to estimate the optimum intensity of anticoagulation, which was between INR 2.0 and 4.0.214 Warfarin targeted at INR 2.0 to 2.5 was not superior to acetylsalicylic acid 150 mg in the AFTER study,215 conceivably since this intensity was insufficient. With even lower intensity of anticoagulation, using 1 or 3 mg/day of warfarin, no benefit over acetylsalicylic acid 160 mg could be detected in the CARS trial.216
TABLE 132-8 EFFECT OF WARFARIN COMPARED TO PLACEBO IN THE PREVENTION OF DEATH AND NONFATAL MYOCARDIAL INFARCTION OR STROKE (=PRIMARY EVENTS) AFTER MYOCARDIAL INFARCTION
LEFT VENTRICULAR DYSFUNCTION
In a retrospective cohort analysis the use of warfarin resulted in a reduced risk of death, primarily those due to cardiac events, and of hospital admission for heart failure.217 Since other studies have shown a relatively low incidence of systemic embolization in chronic heart failure, it has been suggested that the use of warfarin be limited to patients with atrial fibrillation or previous embolic events.218
PERIPHERAL VASCULAR DISEASE
Several studies have demonstrated a benefit of long-term therapy with vitamin K antagonists after bypass surgery in the lower limb with regard to graft function, limb salvage, and patient survival.219,220 and 221 Antiplatelet agents may, however, be at least as effective with less severe side effects for this indication.222,223
Orthopedic surgery confers a particularly high risk of venous thromboembolism, with a frequency of deep vein thrombosis as high as 70 percent. Minidose warfarin (1 mg daily), which has a negligible effect on the INR, does not provide effective prophylaxis in this situation.224 Low-dose warfarin, which prolongs the PT about 1.2 to 1.5 times the control value, is associated with a low rate of symptomatic pulmonary embolism (0.3–0.7%) after total joint arthroplasty,225,226 and 227 but in a randomized trial it was not more effective than acetylsalicylic acid.225 Full-dose warfarin targeted at an INR of 2.0 to 3.0 has been compared with low-molecular-weight heparin (LMWH) in several randomized trials and the efficacy, measured as thrombosis on screening after about 7 to 9 days, was usually superior with LMWH.228,229,230,231 and 232 In some of the studies, warfarin caused less hemorrhage than LMWH,228,231,232 and a meta-analysis of 22 trials with combinations of warfarin, LMWH, or unfractionated heparin reiterated the relative safety of warfarin.233 Several analyses of cost-effectiveness have, however, yielded results in favor of LMWH for arthroplasty of the hip as well as of the knee.234,235,236 and 237
A “two-step” warfarin regimen, beginning with a lower dose 10 to 14 days before arthroplasty and postoperative adjustment to reach an INR of 2.2, did not provide any advantage compared with initiation of therapy the night before surgery.238
Prophylaxis with warfarin after surgery for acetabular or pelvic fractures resulted in an incidence of symptomatic deep vein thrombosis and pulmonary embolism of 3 and 1 percent respectively, with minimal bleeding complications.239
The risk of venous thromboembolism after orthopedic surgery is not eliminated by 7 to 10 days of postoperative prophylaxis, and several studies have investigated the benefit of prolonged prophylaxis at home. In a study of 96 patients after orthopedic surgery, a fixed low dose of warfarin (2 mg/day) was compared with an adjusted higher dose given for 1 month. The regimens appeared equally effective and safe, and the fixed low dose virtually eliminated the need for monitoring.240
For major gynecological surgery, fixed minidose warfarin (1 mg/day) started an average of 20 days before surgery was as effective as, but safer than, warfarin targeted at an INR of 1.5 to 2.5.241
CENTRAL VENOUS CATHETERS
A randomized trial demonstrated that minidose warfarin reduced the risk of venous thrombosis associated with chronic central venous catheters from 38 to 10 percent during 90 days.242 In a retrospective study of patients with central venous catheters for long-term total parenteral nutrition, minidose warfarin was not less effective than a low-dose regimen with PT prolonged to 1.2 to 1.5 times that of control subjects.243 However, for those patients with thrombosis on minidose warfarin, a switch to the higher dose significantly reduced the risk of recurrent thrombosis.243
Although it is more difficult to maintain a stable therapeutic INR (2.0–3.0) in patients with cancer than in patients without cancer,244 the risk of warfarin-induced hemorrhage is similar.245 For patients with metastatic breast cancer receiving chemotherapy, minidose warfarin for 6 weeks, followed by adjusted low-dose warfarin targeted at an INR of 1.3 to 1.9 (mean dose 2.6 mg/day), was effective in reducing the risk of venous thromboembolism (0.7 versus 4.4% with placebo) without increasing the risk of hemorrhage.246
OTHER INDICATIONS FOR PRIMARY PROPHYLAXIS
In patients with membranous nephropathy, prophylaxis against thromboembolism with vitamin K antagonists appears to provide benefits that outweigh the risks.247
Established Venous Thromboembolism Treatment with vitamin K antagonists is started concomitantly with heparin in acute venous thromboembolism (see “Initiation of Therapy,” under “Dosing”). In a randomized trial, a target INR of 2.0 to 2.5 was associated with a significant reduction of hemorrhage without any increase of thromboembolic endpoints when compared to an INR of 3.0 to 4.5.248 A slightly wider range, of INR 2.0 to 3.0, is more convenient and often used,101,249,250 and the incidence of major hemorrhage is 4.7 to 8.8 per 100 patient-years. With a slightly modified range of INR 2.0 to 2.85, this incidence drops to 2.4 per 100 patient-years.99,251 This intensity is also sufficient for patients with inherited thrombophilia or venous thromboembolism in combination with antiphospholipid antibodies.252 In patients with systemic lupus erythematosus, antiphospholipid antibodies, and venous thromboembolism, a higher intensity is, however, required253,254 (see Chap. 128).
Multicenter trials with sufficiently large numbers of patients have shown that, if the duration of secondary prophylaxis is prolonged from 4 weeks to 3 months, the risk of recurrence during 1 year is reduced from 7.8 to 4 percent101; and when it is prolonged from 6 weeks to 6 months, the risk during 2 years is reduced from 18.1 to 9.5 percent.251 These patients were included after the first event of venous thromboembolism, and the prolonged treatment did not cause any increase of major hemorrhages.101,251 In another trial, patients with a second episode of venous thromboembolism were randomized between 6 months and indefinite duration of anticoagulation.99 The risk of recurrence over 4 years was reduced from 20.7 to 2.6 percent, but at the cost of a trend toward more major hemorrhages: 2.7 versus 8.6 percent. After discontinuation of the secondary prophylaxis, there was a recurrence rate of 4 to 5 percent per year for several years.99,251
Risk factors for an increased risk of recurrence include proximal deep vein thrombosis255; pulmonary embolism255; idiopathic thromboembolism or a permanent triggering factor255; hereditary deficiency of antithrombin, protein C, or protein S256; hyperhomocysteinemia257; and antiphospholipid antibodies.252 The latter are also a predictor of an increased risk of cardiovascular death, which justifies long-term secondary prophylaxis.
In pulmonary hypertension, either primary or induced by the anorectic drug aminorex, warfarin has a positive effect on survival.258
A few case reports have described a dramatic positive effect of warfarin on migraine259 and improvement by low doses of warfarin on calcinosis in systemic sclerosis.260 Vitamin K antagonists have been reported to improve survival in small-cell carcinoma of the lung261,262 and to reduce the cancer incidence and mortality in patients with heart disease.263
NOVEL VITAMIN K ANTAGONISTS
Alcohol and ester analogs of (R) -(+)(S)-warfarin have reduced protein binding, which can be utilized for the development of alternative agents with a lower risk of interactions with other drugs.264
OTHER ORAL ANTICOAGULANTS
The oral bioavailability of unfractionated heparin can be increased to 8 percent by addition of delivery agents that improve the gastrointestinal absorption.265 LMWH are of a size that should make oral administration feasible. Sulodexide is composed of 80 percent iduronylglycosaminoglycan sulfate and 20 percent dermatan sulfate, and has almost complete bioavailability after oral administration and an equivalent antithrombotic effect compared with heparin.266,267 Heparan sulfate has been given orally in a study of patients after myocardial infarction.268
INHIBITORS OF COAGULATION FACTOR XA
Direct and selective factor Xa inhibitors for oral use in humans are currently under development and have shown a potent antithrombotic effect with minimal or no influence on the bleeding time in animal models.269,270
INHIBITORS OF THROMBIN
Several low-molecular-weight active-site inhibitors of thrombin are selective and have a high degree of bioavailablity.271,272,273 and 274 A small active-site–directed thrombin inhibitor is not only a potent antithrombotic agent,275 but by being easily incorporated into newly formed thrombi, it enhances the susceptibility of the clot to spontaneous lysis.272 Some of these agents are currently in early-phase clinical trials. A rapid onset of activity, favorable dose-response relationships, renal excretion rather than metabolism by hepatic enzymes, and decreased potential for drug interactions via enzyme competition or protein binding could make these oral agents good candidates for replacement of both heparin and vitamin K antagonists in the prophylaxis and treatment of thrombotic disorders.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn