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CHAPTER 133 HEPARIN, HIRUDIN, AND RELATED AGENTS

CHAPTER 133 HEPARIN, HIRUDIN, AND RELATED AGENTS
Williams Hematology

CHAPTER 133 HEPARIN, HIRUDIN, AND RELATED AGENTS

GARY E. RASKOB
RUSSELL D. HULL
GRAHAM F. PINEO

Heparin

Pharmacology

Laboratory Monitoring of Therapy

Clinical Use

Antidote to Heparin
LMW Heparin

Pharmacology

Clinical Use
Danaparoid

Pharmacology

Clinical Use
Hirudin and Derivatives

Pharmacology

Clinical Use
Small-Molecule Direct Thrombin Inhibitors
Chapter References

This chapter provides an overview of the pharmacology and clinical use of heparin and hirudin and related anticoagulant agents including low-molecular-weight (LMW) heparin, the glycosaminoglycan mixture danaparoid, the semisynthetic hirudin fragment bivalirudin (Hirulog), and the small-molecule direct inhibitors of thrombin such as argatroban. The sections on clinical use emphasize the major indications including the treatment of venous thromboembolism, the treatment of acute coronary syndromes, and the treatment of patients with heparin-induced thrombocytopenia. The recommendations for clinical use are linked to the strength of the evidence from clinical trials. Heparin has been the standard initial treatment for acute deep-vein thrombosis or pulmonary embolism for many years and has an important role in the treatment of patients with acute coronary syndromes. Heparin treatment for these indications requires laboratory monitoring of the anticoagulant effect and dose adjustment in the individual patient. The activated partial thromboplastin time (aPTT) is the test most commonly used to monitor heparin treatment for venous thromboembolism or acute coronary syndromes. The effectiveness of intravenous heparin for preventing recurrent venous thromboembolism depends on achieving an aPTT response above the lower limit of the therapeutic range during the first 24 h of therapy. Validated heparin protocols are more successful for establishing adequate heparinization than intuitive ordering by the clinician. LMW heparin is at least as effective and possibly more effective than unfractionated heparin for the treatment of venous thromboembolism or acute coronary syndromes. LMW heparin is given by subcutaneous injection once or twice daily and does not require laboratory monitoring of the anticoagulant effect. LMW heparin treatment enables many patients with uncomplicated venous thromboembolism to be treated in an outpatient setting and is more cost-effective than intravenous unfractionated heparin in such patients. LMW heparin is also cost-effective compared to intravenous heparin treatment of patients with acute coronary syndromes. Clinical trials of hirudin and bivalirudin in patients with acute coronary syndromes have yielded disappointing results. Hirudin has a relatively narrow therapeutic range. The major indication for hirudin therapy is likely to be for patients with heparin-induced thrombocytopenia who require anticoagulant treatment. Danaparoid is the drug of choice for the treatment of pregnant patients with heparin-induced thrombocytopenia who require ongoing anticoagulant therapy. The role of the small-molecule direct thrombin inhibitors remains to be determined by randomized clinical trials.

Acronyms and abbreviations that appear in this chapter include: ACT, activated clotting time; aPTT, activated partial thromboplastin time; LMW, low-molecular-weight.

HEPARIN
PHARMACOLOGY
Heparin is a glycosaminoglycan composed of chains of alternating residues of D-glucosamine and iduronic acid. Heparin molecules vary in chain length and therefore in molecular mass. Heparin that is available for clinical use is a mixture of molecules which vary in mass from 5000 to 30,000 daltons, with an average of 15,000 daltons. This average molecular mass corresponds to a chain length of approximately 50 monosaccharide units. The mass (chain length) of a heparin molecule is an important determinant of both anticoagulant activity and pharmacokinetic properties.1
Heparin exerts an anticoagulant effect by enhancing the inactivation by antithrombin III of thrombin, factor Xa, and factor IXa. The major anticoagulant effect is due to a unique pentasaccharide which has a high affinity for binding to antithrombin III.1 This pentasaccharide is present in only about one-third of the molecules of the heparin mixtures used in clinical practice. The pentasaccharide has been synthesized and is currently undergoing evaluation as an antithrombotic agent in clinical trials.
The inhibition of thrombin by heparin is different from the inhibition of factor Xa.1 Heparin enhances the inhibition of thrombin by forming a ternary complex in which heparin binds directly to both antithrombin III and thrombin. The inhibition of factor Xa by the heparin/antithrombin III complex does not require heparin to bind directly to factor Xa in a ternary complex. Heparin molecules that contain less than 18 saccharide units are unable to bind thrombin and antithrombin III simultaneously. These LMW heparin molecules are unable to augment the inhibition of thrombin by antithrombin III but retain the ability to augment the inhibition of factor Xa (see “LMW Heparin”).
The heparin/antithrombin III complex is a weak inhibitor of thrombin bound to fibrin and of factor Xa when incorporated within the prothrombinase complex.2 These in vitro biochemical properties have been suggested as an explanation for the limited antithrombotic efficacy of heparin in the clinical settings of high-risk coronary angioplasty2,3 but remain unproved.
The pharmacokinetics of heparin after intravenous injection of a bolus dose can be described by a two-compartment model consisting of a rapid, zero-order phase, followed by a slower, first-order elimination phase.4 The initial zero-order phase is thought to be due to rapid binding and uptake of heparin by endothelial cells and macrophages. These cells internalize the heparin and depolymerize it into LMW heparin fractions. This process is saturable within the range of heparin doses used in clinical practice, and, therefore, the half-life of heparin in plasma is dose-dependent.4,5 The plasma half-life of heparin increases from approximately 30 min after an intravenous dose of 25 units/kg to 150 min following a dose of 400 units/kg. The second phase of heparin removal from plasma reflects the renal clearance of the LMW molecules. Heparin binds to several plasma proteins including histidine-rich glycoprotein, vitronectin, fibronectin, fibrinogen, and lipoproteins.1 Heparin also binds to platelet factor 4 and to high-molecular-weight von Willebrand factor.
LABORATORY MONITORING OF THERAPY
The aPTT is the test most commonly used in clinical practice to monitor the anticoagulant effect of heparin in patients with established venous thromboembolism or acute coronary syndromes. The aPTT is sensitive to plasma heparin concentrations of 0.1 units/ml or more. However, the different reagents used to measure aPTT and the equipment used affect the sensitivity of the assay to heparin. For this reason, it is recommended that the therapeutic range be established by each laboratory by calibrating the aPTT to a plasma heparin concentration of 0.2 to 0.4 units/ml by protamine sulfate titration or 0.3 to 0.7 units/ml by the factor Xa assay.1 The aPTT is usually prolonged above the upper measurable limit (approximately 150 s) at plasma heparin concentrations of 1.0 units/ml or more. The activated clotting time (ACT) has a graded response to heparin concentrations of 1.0 to 5.0 units/ml. The ACT is used to monitor the effect of heparin in patients who receive high heparin doses such as those undergoing coronary angioplasty or cardiac bypass surgery.
There is considerable variation in the aPTT response to a given plasma heparin concentration among patients with venous thromboembolism or acute coronary syndromes.1 The patient variables which influence the aPTT response include age, sex, the extent of heparin uptake by endothelial cells and macrophages, and the levels of acute-phase reactant proteins, particularly factor VIII.1,5 For example, the aPTT response to a given heparin concentration may be diminished by elevated levels of factor VIII which can occur postoperatively or in association with acute illness, malignancy, or pregnancy.
Therefore, in patients with venous thromboembolism and acute coronary syndromes, heparin therapy must be individualized by monitoring the anticoagulant effect and adjusting the heparin dose to achieve the target aPTT therapeutic range.
CLINICAL USE
Heparin has been the standard initial therapy for acute deep-vein thrombosis or pulmonary embolism and is widely used to treat patients with acute coronary syndromes. Heparin is also used to prevent thrombosis during vascular surgery or angioplasty and to prevent ex vivo thrombi during cardiopulmonary bypass surgery. Heparin is also indicated for preventing venous thromboembolism following surgery and in medical patients.
The doses of heparin that are required to treat patients with established venous or arterial thromboembolism are greater than the doses required to prevent the development of venous thromboembolism in high-risk patients. A low dose of heparin given subcutaneously, such as 5000 units every 8 or 12 h, continues to be one of the preferred approaches for preventing venous thromboembolism in moderate- to high-risk patients undergoing general abdominal or thoracic surgery, in patients with acute ischemic stroke with leg paralysis, and in general medical patients.6 Evidence-based reviews of the use of heparin in cardiovascular surgery7 and coronary angioplasty8 have been published.
VENOUS THROMBOEMBOLISM
Heparin therapy for established venous thromboembolism can be given intravenously or subcutaneously. Continuous infusion is the preferred approach for initial treatment because of the need to achieve a rapid therapeutic anticoagulant effect.9 The appropriate regimen of subcutaneous heparin needed to ensure an adequate and rapid effect remains unknown. Two protocols for initial intravenous heparin treatment of venous thromboembolism have been validated in randomized clinical trials measuring the outcomes of recurrent thromboembolism and major bleeding.10,11 These protocols utilize an initial intravenous bolus of 5000 units or 75 units/kg, followed by a maintenance infusion of 1250 to 1660 units/h10 or 18 units/kg per hour.11 The subcutaneous route of administration is used when heparin is given for the long-term treatment of venous thromboembolism or when intravenous access cannot be obtained.
An analysis of patients entered into a series of three consecutive double-blind randomized trials evaluating initial heparin therapy showed that patients who failed to achieve the lower limit of the therapeutic range for the aPTT were at increased risk of recurrent venous thromboembolism during the subsequent 3 months.9,12 Among patients treated with an initial intravenous heparin infusion of 30,000 units per 24 h (after a bolus of 5000 units), 4 of 19 patients (21%) whose aPTTs were subtherapeutic during the initial 24 h had recurrent venous thromboembolism, compared with 24 of 392 patients (6%) who achieved an aPTT result above the lower limit of the therapeutic range within 24 h (P = 0.03). Of the recurrent events, 75 percent occurred between 2 and 12 weeks after the initial diagnosis, despite treatment with oral anticoagulants. These data indicate that the initial heparin treatment impacts the patient’s long-term outcome for at least 3 months in the presence of adequate long-term anticoagulant therapy.12 A previous literature review13 was unable to document the relationship between adequate initial therapy and antithrombotic effectiveness because of missing data on the anticoagulant response or clinical outcome in many of the published reports. This literature review also reported a wide 95 percent confidence interval for the odds ratio for recurrent thromboembolism among patients who were or were not subtherapeutic during the initial 24 h of heparin treatment.13
The above findings are independently supported by the results of a randomized trial comparing different intensities of initial heparin treatment by continuous infusion.11 In the patient group randomized to receive an initial heparin infusion of 1000 units/h, the aPTT results were subtherapeutic in 23 percent at 24 to 48 h, and this treatment group had a 25 percent frequency of recurrent venous thromboembolism, compared with a 5 percent recurrence rate (P = 0.002) in the more intense heparin infusion group who received weight-adjusted dosing, and in whom only 3 percent of patients were subtherapeutic at 24 h (P = 0.002). The importance of adequate initial heparin administration in patients with venous thromboembolism is summarized in Table 133-1. The results are consistent across independent studies.11,14,15 There are similar high rates of recurrent venous thromboembolism (19% to 25%) among patients in whom the anticoagulant regimen fails to achieve an aPTT above the lower limit of the therapeutic range within 24 h, and there are consistent reductions in the rates of recurrent thromboembolism achieved by adequate heparin therapy (Table 133-1).

TABLE 133-1 IMPORTANCE OF ADEQUATE INITIAL HEPARIN ADMINISTRATION FOR VENOUS THROMBOEMBOLISM

The use of a validated heparin protocol will lessen the likelihood of delayed adequate heparinization.10,11 The key steps used by such protocols are adequate initial heparin infusion doses (1250 to 1600 units/h or 18 units/kg per hour) and frequent aPTT measurements in the first 24 h to identify rapidly the individual patient’s heparin requirements. Although such heparin protocols are more successful in establishing adequate heparinization than intuitive ordering by the clinician,10,11,16 some patients may still receive suboptimal therapy. This reflects a practical limitation of unfractionated heparin. The difficulties of heparin administration are compounded by the practical difficulties of standardizing aPTT testing and the therapeutic range. Therapy with LMW heparin, which does not require monitoring and dose adjustment, is the practical solution to these difficulties (see “LMW Heparin”).
Adjusted-dose subcutaneous heparin is the regimen of choice for the long-term treatment of established venous thromboembolism in pregnant patients and in patients in whom warfarin cannot be used or has failed. The heparin dose is adjusted during the first few days of subcutaneous therapy to achieve an aPTT above the lower limit of the therapeutic range.17 The subcutaneous heparin dose can be estimated from the patient’s intravenous heparin requirements. A general guide is to administer two-thirds of the patient’s total daily intravenous heparin dose in divided subcutaneous doses. For example, if the patient required 30,000 units per 24 h to achieve a therapeutic aPTT response, then the estimated subcutaneous regimen for long-term treatment would be 10,000 units given every 12 h. The aPTT is measured 6 h after the morning subcutaneous injection. The heparin dose is adjusted to maintain this aPTT above the lower limit of the therapeutic range.17 Once a stable dose has been identified, the dose can be fixed for the duration of therapy, except in pregnant patients, due to changing heparin requirements throughout the course of pregnancy. The aPTT should be measured at regular intervals in pregnant patients to ensure that adequate heparin treatment is maintained. It is not uncommon for pregnant patients to develop relatively large daily heparin requirements as pregnancy progresses (e.g., 40,000 to 50,000 units daily).
ACUTE CORONARY SYNDROMES
The objectives of heparin treatment in patients with acute coronary syndromes are to reduce the risk of death, myocardial infarction, mural thrombosis, systemic embolism, and recurrent ischemia.18
In patients with unstable angina, intravenous heparin by continuous infusion is effective for preventing myocardial infarction and death and is more effective than aspirin alone for preventing recurrent ischemic symptoms. There is a high rate of reactivation of ischemia early after stopping intravenous heparin if aspirin is not given.19 The reactivation of ischemia is less frequent if aspirin is given before heparin is discontinued. The combined use of heparin and aspirin is preferred in patients with unstable angina.18 Sufficient heparin should be given to prolong the aPTT to 1.5 to 2 times control. A practical regimen is an intravenous bolus of 5000 units or 75 units/kg, followed by a continuous intravenous infusion of 1250 units/h.18 Heparin therapy should be continued for at least 48 h or until the unstable pain pattern resolves.
Heparin is also indicated for patients with acute myocardial infarction. Every patient with acute myocardial infarction should receive at least low-dose heparin therapy to prevent venous thromboembolism.18 However, in current practice, most patients will receive more intensive heparin therapy, either as adjunctive treatment to thrombolysis or because they are at high risk for development of mural thrombosis and systemic embolism due to large anterior Q-wave infarction, left ventricular dysfunction, echocardiographic evidence of mural thrombosis, atrial fibrillation, or a history of systemic or pulmonary embolism. The recommended regimen is intravenous heparin given as an initial bolus of 5000 units or 75 units/kg, followed by a maintenance infusion of 1250 units/h, adjusted to maintain the aPTT between 1.5 and 2 times control.18 Heparin is continued for 48 h in patients who have received thrombolytic therapy with recombinant tissue plasminogen activator or reteplase. In patients who receive thrombolysis with streptokinase or APSAC, heparin should only be given to those patients who have risk factors for systemic embolism. Patients at high risk for developing mural thrombosis and systemic embolism because of the risk factors listed above should continue anticoagulant treatment for up to 3 months.18 Oral anticoagulant therapy with warfarin, overlapped with heparin and adjusted to maintain the INR between 2.0 and 3.0, is the preferred approach for most patients.
The optimal use of intravenous heparin or LMW heparin (see below) together with intravenous platelet glycoprotein (GP) IIb/IIIa receptor inhibitors is currently unknown (see Chap. 131). This issue will be increasingly important with the more widespread use of the platelet GPIIb/IIIa receptor inhibitors as initial therapy for patients with acute coronary syndromes. If abciximab is used during coronary angioplasty, less intensive intravenous heparin (bolus of 70 units/kg repeated to maintain the ACT above 200 s) reduces the risk of major bleeding without loss of antithrombotic effectiveness compared to the more intense heparin regimens traditionally used for angioplasty (bolus 10,000 to 20,000 units and maintaining ACT of 300 to 350 s).20
SIDE EFFECTS
The key side effects of short-term heparin therapy are bleeding and thrombocytopenia. Osteoporosis is a potential complication of long-term heparin treatment. Heparin may cause elevation of transaminase levels, but these elevations are of unknown clinical significance and usually return to normal after heparin is discontinued. Awareness of this biochemical effect is important so as to avoid unnecessary interruption of heparin therapy and unnecessary liver biopsies in patients who may develop elevated transaminases during heparin treatment. Additional rare side effects include hypersensitivity, skin reactions including necrosis, alopecia, and hyperkalemia due to hypoaldosteronism.
Bleeding complications may be categorized as major or minor according to standard international criteria.21 Major bleeding is defined as clinically overt bleeding resulting in a decline of hemoglobin of 2 g/dl or more (or transfusion of 2 or more units of packed red cells), or bleeding which is intracranial or retroperitoneal. The rates of major bleeding reported from contemporary clinical trials of intravenous heparin treatment for venous thromboembolism range from 0 to 7 percent, and the rates of fatal bleeding range from 0 to 2 percent.22 The presence or absence of underlying risk factors for bleeding have a marked impact on the incidence of major bleeding. Patients at high risk for major bleeding are those who have had recent surgery or trauma within the previous 14 days; those with a history of gastrointestinal bleeding, peptic ulcer disease, or genitourinary bleeding; and those with conditions predisposing to bleeding such as thrombocytopenia, liver disease, multiple invasive lines, etc. The risk of major bleeding is also increased in patients over 70 years of age. The available data indicate that the patient-related factors described above are stronger determinants of the risk of major bleeding than the heparin dose or aPTT response. Thus, the incidence of major bleeding is 10 percent among patients with one or more of these risk factors in whom the intravenous heparin infusion is begun at a dose of 1250 units/h, compared with only 1 percent among patients in whom all of the risk factors are absent, and who receive a larger initial infusion dose (1660 units/h).23 To date, no study has definitively established a relationship between an excessively prolonged aPTT and increased risk of major bleeding for patients with venous thromboembolism or acute coronary syndromes who do not receive thrombolysis or abciximab.1
Heparin may cause thrombocytopenia (see Chap. 117). Two types of heparin-induced thrombocytopenia have been described: (1) early, nonimmune thrombocytopenia that often resolves while heparin is continued and does not result in clinically important consequences,1 and (2) immune-mediated thrombocytopenia which usually occurs after 5 days of heparin treatment but may occur earlier in patients who have been previously exposed to heparin.24 The immune form of heparin-induced thrombocytopenia may develop with prophylactic or therapeutic doses given by any route of administration. Heparin-induced immune thrombocytopenia is mediated by an immunoglobulin G (IgG) antibody directed against a complex of platelet factor 4 and heparin,25,26 although other target antigens may also be important.27
The immune type of heparin-induced thrombocytopenia may be accompanied by extension of preexisting venous thromboembolism or development of new arterial thrombosis that may precede or coincide with the fall in the platelet count.28,29 These complications have been associated with a high incidence of limb amputation and a high mortality rate.29 Heparin in all forms should be discontinued when the diagnosis of heparin-induced thrombocytopenia is made on clinical grounds. The laboratory diagnosis of heparin-induced thrombocytopenia is often not achievable because the definitive platelet activation assays may not be available and are limited by a slow turnaround time. Most importantly, the safety of continuing heparin treatment in patients with negative results by any of the currently available assays has not been established by properly designed prospective studies. The identification of additional target antigens for heparin-induced thrombocytopenia suggests that it may not be safe to continue heparin because an ELISA assay for antibodies to the heparin/PF4 complex is negative. For patients with acute heparin-induced thrombocytopenia who require continued anticoagulant treatment, the recommended options include danaparoid sodium or recombinant hirudin (both discussed later in this chapter). LMW heparin is not recommended for anticoagulant treatment in patients with acute heparin-induced thrombocytopenia.
Osteoporosis may occur as a side effect of long-term heparin therapy (usually more than 3 months). The earliest clinical manifestation of heparin-associated osteoporosis is usually nonspecific low-back pain primarily involving the vertebrae or ribs; patients may also have spontaneous fractures in these areas. The incidence of symptomatic fractures is estimated to be about 2 percent. Up to one-third of patients treated with long-term heparin may have subclinical reductions in bone density. It is unknown if these patients are predisposed to an increased risk of future fractures.
ANTIDOTE TO HEPARIN
The anticoagulant effect of heparin can be rapidly neutralized by the intravenous injection of protamine sulfate. Protamine sulfate is indicated for selected patients with major bleeding. The appropriate neutralizing dose of protamine sulfate depends on the dose of heparin, the route of administration, and the time since the last dose was given. If protamine sulfate is used within minutes of an intravenous heparin injection, a full neutralizing dose should be given (1 mg protamine sulfate per 100 units heparin). For example, an intravenous bolus of 5000 units of heparin would require a protamine sulfate dose of 50 mg. Doses of protamine sulfate larger than 50 mg are rarely needed because heparin is cleared quickly from plasma with a half-life of approximately 60 min. After a subcutaneous injection of heparin, repeated small doses of protamine may be required because of prolonged heparin absorption from the subcutaneous depot.
LMW HEPARIN
PHARMACOLOGY
LMW heparin is prepared by depolymerization of unfractionated heparin using chemical or enzymatic methods. Several LMW heparins have been prepared for clinical use (Table 133-2). These preparations have an average molecular mass of 4000 to 6000 daltons, with a range of 1000 to 10,000 daltons.1

TABLE 133-2 LOW-MOLECULAR-WEIGHT HEPARINS

There are important pharmacologic differences between LMW heparins and unfractionated heparin. These include a reduced ability to catalyze the inhibition of thrombin in vitro while retaining the ability to inhibit the activity of factor Xa (a so-called higher anti-Xa to anti-IIa ratio).1 The clinical relevance of this pharmacologic property is uncertain. LMW heparins exhibit less binding than unfractionated heparin to a variety of plasma proteins and to cells including platelets, endothelial cells, macrophages, and possibly osteoblasts.1 Most plasma proteins that bind unfractionated heparin do not bind or neutralize LMW heparin. The reduced binding of LMW heparin to plasma proteins contributes to its more predictable anticoagulant dose response. The reduced binding of LMW heparin to endothelial cells and macrophages contributes to its longer plasma half-life (see below). LMW heparin causes less thrombocytopenia than unfractionated heparin28 when given to patients who have not previously received heparin, although thrombocytopenia may still occur with LMW heparin. LMW heparin may also be less likely to cause clinically important osteoporosis than unfractionated heparin.30
The pharmacokinetic properties of LMW heparin make it possible to give this agent subcutaneously once or twice daily without the need for laboratory monitoring of the anticoagulant response or dose adjustment. These pharmacokinetic properties include a very high bioavailability (greater than 90%) after subcutaneous injection, a longer half-life than unfractionated heparin, and much less interindividual variation in the anticoagulant response to a given dose.1 The anticoagulant response (anti-Xa activity) to a fixed dose of LMW heparin is highly correlated with the patient’s body weight. The regimens of LMW heparin used for the treatment of patients with established venous thromboembolism or patients with acute coronary syndromes are based on units/kg body weight or on body weight range category. LMW heparin is cleared mainly by the kidneys, and therefore clearance of LMW heparin is reduced in patients with renal failure.1 The anticoagulant (anti-Xa) effect of LMW heparin is not completely neutralized by protamine sulfate, but treatment with protamine sulfate may still decrease the hemorrhagic effect of LMW heparin.
There are biochemical and pharmacologic differences between the LMW heparin preparations. However, the clinical relevance of these differences in terms of effectiveness or safety of treatment remains unknown. The different LMW heparin preparations are not interchangeable.31 Each LMW heparin preparation must be evaluated by clinical trials measuring the outcomes of thromboembolism, bleeding, and mortality. The decision to use a specific LMW heparin should be based on the available clinical trial data for that preparation.
CLINICAL USE
LMW heparin has been extensively evaluated for the prevention of venous thromboembolism in high-risk patients, for the treatment of established deep-vein thrombosis and pulmonary embolism, and for the treatment of patients with acute coronary syndromes.
VENOUS THROMBOEMBOLISM
The results of the major clinical outcome studies32,33,34,35,36,37,38,39 and 40 evaluating LMW heparin for the initial treatment of venous thromboembolism are summarized in Table 133-3. The findings indicate that LMW heparin is at least as effective and safe as intravenous unfractionated heparin. LMW heparin enables outpatient therapy for many patients with uncomplicated deep-vein thrombosis. In the two randomized trials evaluating home treatment,36,37 36 to 48 percent of patients receiving LMW heparin were never admitted to the hospital, and 40 percent were discharged from the hospital after a shorter hospital stay (2 to 3 days versus 5 days for intravenous unfractionated heparin). Outpatient LMW heparin provides a potential for major cost savings to the health-care system compared to therapy with intravenous heparin in the hospital.41

TABLE 133-3 MAJOR CLINICAL OUTCOME TRIALS OF LMW HEPARIN FOR THE TREATMENT OF DEEP-VEIN THROMBOSIS AND PULMONARY EMBOLIS

LMW heparin treatment of deep-vein thrombosis is effective when given either twice daily or once daily.32,33,34,35,36,37,38,39 and 40,42 Treatment with once-daily subcutaneous regimens are more convenient for the patient and the care providers. Emerging data indicate that when an equivalent total daily dose is given once daily, rather than in a divided dose twice daily, antithrombotic effectiveness may be improved.40 Further, the only clinical trial to date suggesting superior efficacy of LMW heparin treatment to intravenous heparin utilized a once-daily regimen.33 Treatment with LMW heparin as a single daily dose rather than divided doses maximizes the intensity of an early antithrombotic effect which was shown to be important for clinical effectiveness of unfractionated heparin.9,12 Finally, there is no evidence from clinical trials of patients with venous thromboembolism that giving an equivalent total daily dose in divided doses rather than a single dose enhances safety in terms of bleeding complications. The regimens of LMW heparin for the treatment of established venous thromboembolism evaluated by clinical outcome studies are listed in Table 133-4.

TABLE 133-4 REGIMENS OF LMW HEPARIN FOR THE TREATMENT OF VENOUS THROMBOEMBOLISM

LMW heparin has been less extensively evaluated for the initial treatment of patients with symptomatic pulmonary embolism. Two randomized trials indicate that two different LMW heparin regimens are as effective and safe as continuous intravenous unfractionated heparin in patients with submassive symptomatic pulmonary embolism.38,39 The two LMW heparin regimens evaluated were reviparin twice daily in doses given according to weight category (Table 133-4) and tinzaparin 175 units/kg once daily. This regimen of tinzaparin has also been shown to be more effective than intravenous unfractionated heparin for treatment of patients with pulmonary embolism who have underlying proximal deep-vein thrombosis.43
ACUTE CORONARY SYNDROMES
LMW heparin is effective for treatment of patients with acute coronary syndromes.18 The two LMW heparin regimens evaluated were enoxaparin 1 mg/kg twice daily or dalteparin 120 units/kg twice daily. The clinical trials indicate that LMW heparin is at least as effective as intravenous unfractionated heparin. Two large randomized trials indicate that the enoxaparin regimen is more effective for reducing the incidence of the composite outcome of death, myocardial infarction, or recurrent ischemia.44,45 The enoxaparin regimen reduced the incidence of recurrent ischemic events requiring reintervention with an absolute risk reduction of 4 percent compared to intravenous unfractionated heparin. This benefit was sustained for up to 1 year. The use of enoxaparin is cost-effective by comparison to intravenous unfractionated heparin.46
DANAPAROID
PHARMACOLOGY
Danaparoid sodium is a mixture of glycosaminoglycans including heparan sulfate, dermatan sulfate, and chondroitin sulfate. Danaparoid was previously known as Org 10172 and lomoparan. The predominant anticoagulant effect of danaparoid is due to its anti-factor-Xa activity.
Danaparoid can be given either by intravenous infusion or subcutaneous injection. The plasma half-life of the anti-factor-Xa activity of danaparoid is approximately 24 h. Danaparoid is eliminated mainly by the kidneys. There is no known antidote for danaparoid.
There may be in vitro cross-reactivity to heparin-induced thrombocytopenia antibodies with some of the glycosaminoglycans contained in danaparoid. However, this in vitro cross-reactivity is of uncertain clinical relevance because a randomized clinical trial indicates danaparoid is effective for treatment of patients with acute heparin-induced thrombocytopenia,47 and the rate of recovery of platelet counts in patients with heparin-induced thrombocytopenia during danaparoid treatment is unrelated to the presence of in vitro cross-reactivity.48
CLINICAL USE
Danaparoid has been evaluated by randomized clinical trials for the prevention of deep-vein thrombosis,6,49 for the treatment of established deep-vein thrombosis,50 and for the treatment of patients with acute heparin-induced thrombocytopenia.47 In this latter study, danaparoid was more effective than dextran.47 The experience with danaparoid in a compassionate-use treatment program for heparin-induced thrombocytopenia has also been published.51
The major indications for danaparoid are treatment of patients with acute heparin-induced thrombocytopenia who require ongoing anticoagulation and for the prevention of thromboembolism in patients with a past history of heparin-induced thrombocytopenia. Danaparoid is the drug of choice for the prevention or treatment of thromboembolism in pregnant patients with a history of heparin-induced thrombocytopenia.
Danaparoid is given by intravenous infusion when rapid therapeutic anticoagulation is required. An intravenous bolus is given followed by a maintenance infusion. The bolus dose differs by patients’ body weight category: 1500 units if less than 60 kg, 3000 units for patients 75 to 90 kg, and 3750 units for patients weighing more than 90 kg.1 Following injection of the bolus, continuous infusion is commenced at a rate of 400 units/h for the first 4 h, then 300 units/h for the next 4 h.1 Thereafter, a maintenance infusion of 150 to 200 units/h is given. This maintenance infusion is adjusted to maintain the plasma anti-factor Xa level between 0.5 and 0.8 units/ml. An alternative approach for maintenance treatment is to administer a subcutaneous injection of 1500 units every 8 to 12 h.
The recommended regimen when danaparoid is used for preventing the development of thromboembolism is 750 to 1500 units every 8 to 12 h depending on the patient’s weight. The recommended regimens are 750 units every 12 h for patients less than 75 kg, 750 units every 8 h for patients between 75 and 90 kg, and 1500 units every 12 h for patients more than 90 kg.1
HIRUDIN AND DERIVATIVES
PHARMACOLOGY
Hirudin is a 65–amino acid polypeptide produced by the salivary gland of the medicinal leech Hirudo medicinalis. Hirudin is the most potent naturally occurring specific inhibitor of thrombin.52 Hirudin directly inactivates thrombin by forming a 1:1 stoichiometric complex with thrombin at two specific sites: an N-terminal domain that binds to the active site of thrombin and a C-terminal domain, which binds to the main fibrinopeptide-binding region on thrombin.52,53 Natural hirudin, recombinant hirudin, and the synthetic analogue Hirulog (bivalirudin) all contain these two binding sites.
Hirudin has been produced by recombinant DNA technology. Recombinant hirudin is not sulfated at tyrosine residue 63 and, as a result, has a tenfold reduced affinity for thrombin.54 Bivalirudin (Hirulog) is a 20–amino acid semisynthetic peptide analogue of hirudin.55 Bivalirudin is a potent thrombin inhibitor that differs from hirudin because it produces only transient inhibition of the active site of thrombin.
Theoretical advantages of hirudin over heparin have been proposed. Although both hirudin and heparin-antithrombin III complex inhibit thrombin enzymatic activity, hirudin is more effective in inhibiting the positive feedback mechanisms of thrombin that promote further thrombin generation, e.g., factor V activation and factor VIII activation.52,53 Hirudin and the analogues effectively inhibit clot-bound thrombin as well as fluid-phase thrombin, whereas the heparin-antithrombin III complex is a weak inhibitor of clot-bound thrombin.2 This may provide an advantage in suppressing the activity of thrombin after vessel injury, such as occurs in angioplasty, and inhibiting clot-bound thrombin after thrombolysis or in venous thromboemboli. Experimental studies indicate that hirudin is capable of suppressing platelet-rich arterial thrombus formation, although at much higher concentrations than are required to suppress venous thrombosis.3 However, experimental animal studies indicate that hirudin produces more bleeding than heparin when these drugs are used in doses that achieve an equivalent aPTT ratio.56 Moreover, since there is a very flat relationship between the hirudin concentration in plasma and the aPTT response, even a small increase in the aPTT ratio within the therapeutic range of 1.5 to 2.5 results in a marked increase in experimental bleeding with hirudin, but not with heparin.56 These observations help to explain the results from early clinical trials with hirudin which documented very high rates of intracranial and major bleeding when hirudin was given in doses adjusted to achieve an aPTT response equivalent to the traditional therapeutic range for heparin (aPTT ratio 1.5 to 2.5).57,58 and 59 A recombinant hirudin known as lepirudin has recently been approved for the treatment of heparin-induced thrombocytopenia. Lepirudin is given intravenously, is cleared by the kidneys, and has a plasma half-life of 1.3 h. There is no known antidote. Up to 50 percent of patients develop IgG antihirudin antibodies.60
The anticoagulant effect of lepirudin is monitored using the aPTT. The antihirudin antibodies may alter the anticoagulant effect, and ongoing monitoring is required in patients receiving lepirudin.
CLINICAL USE
Hirudin has been extensively evaluated by randomized clinical trials in patients with acute coronary syndromes.57,58 and 59,61,62 and 63 It has been evaluated in patients undergoing coronary angioplasty64 and for the prevention of deep-vein thrombosis after total hip replacement.65 Lepirudin has been evaluated in an historical-control study for the treatment of patients with heparin-induced thrombocytopenia.66 Bivalirudin has been evaluated by a randomized clinical trial in patients undergoing coronary angioplasty for unstable or postinfarction angina.67
The initial clinical trials of hirudin in patients with acute coronary syndromes documented high rates of intracranial bleeding in patients who also received thrombolytic therapy.57,58 and 59 In these studies, hirudin was given in doses that produced an aPTT similar to that achieved with therapeutic doses of intravenous heparin. Subsequent clinical trials using lower doses of hirudin failed to demonstrate that hirudin was superior to heparin in patients with acute myocardial infarction who also received thrombolysis.61,62 The recently completed large Oasis II trial suggests that lepirudin may be marginally more effective than heparin for preventing cardiovascular death or new myocardial infarction in patients with acute myocardial ischemia without ST-segment elevation.63 At 7 days, the primary outcome of cardiovascular death or new myocardial infarction occurred in 4.2 percent of 5058 patients given intravenous heparin, compared with 3.6 percent of 5083 patients given lepirudin (P = 0.077). Long-term follow-up will be required to determine if this potential marginal benefit persists. The potential benefit was offset by an increase in major bleeding from 0.7 percent with intravenous heparin to 1.2 percent with lepirudin. The clinical trials to date indicate that hirudin is not a major advance in antithrombotic treatment of acute coronary syndromes. LMW heparin treatment has achieved larger absolute risk reductions in outcomes, and these improved outcomes persist for up to 1 year.68 LMW heparin is easier to use, does not require anticoagulant monitoring, and is much less expensive.
The major indication for lepirudin therapy is for the treatment of patients with acute heparin-induced thrombocytopenia. An intravenous bolus of 0.4 mg/kg is given with a maintenance infusion of 0.15 mg/kg per hour. The infusion dose is adjusted to maintain an aPTT ratio of 1.5 to 2.5. The first aPTT is measured 4 h after starting the infusion, and subsequent aPTTs should be measured at least once daily. The dose should be reduced in patients with renal impairment (creatinine clearance below 60 ml/min or serum creatinine above 1.5 mg/dl). The recommended initial infusion doses for patients with renal impairment are 0.075 mg/kg per hour for a creatinine clearance of 45 to 60 ml/min, 0.045 mg/kg per hour for a creatinine clearance of 30 to 44 ml/min, and 0.0225 mg/kg per hour for creatinine clearance of 15 to 29 ml/min.
Bivalirudin has been evaluated in a randomized trial of 4098 patients undergoing angioplasty for unstable or postinfarction angina.67 Bivalirudin was not more effective than heparin for reducing the incidence of the primary outcome, which was the cluster outcome of death in the hospital, myocardial infarction, or abrupt vessel closure. Among the prospectively stratified subgroup of patients with postinfarction angina, bivalirudin was more effective for reducing the risk of immediate ischemic complications, with a lower risk of major bleeding. However, the benefit was no longer present at 6 months.
SMALL-MOLECULE DIRECT THROMBIN INHIBITORS
Several LMW direct inhibitors of the active site of thrombin have been developed.69 These include argatroban, napsagatran, inogatran, melagatran, and L372,460. All are potent noncovalent inhibitors of thrombin.69 The agent L372,460 can be given orally and has a relatively long half-life.
Argatroban has been evaluated by an historical-controlled study in patients with heparin-induced thrombocytopenia.1 This study showed a higher mortality among the patients treated with argatroban. Although this may be due to differences in the patients between the treatment groups, a possible drug effect as the cause of this excess mortality cannot be excluded. For this reason, and because alternatives are available (danaparoid sodium and lepirudin), argatroban should not be used. Further clinical trials are required to determine the therapeutic role of the small-molecule direct-acting thrombin inhibitors.
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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