The main adverse effects of heparin therapy include bleeding, thrombocytopenia, and osteoporosis. Patients at particular risk of bleeding are those who have had recent surgery or trauma, or who have other clinical factors which predispose to bleeding on heparin, such as peptic ulcer, occult malignancy, liver disease, hemostatic defects, age >65 years, and female gender.
The management of bleeding on heparin will depend on the location and severity of bleeding, the risk of recurrent VTE and the APTT; heparin should be discontinued temporarily or permanently. Patients with recent VTE may be candidates for insertion of an inferior vena cava filter. If urgent reversal of heparin effect is required, protamine sulphate can be administered.12
Heparin-induced thrombocytopenia is a well-recognized complication of heparin therapy, usually occurring within five to 10 days after heparin treatment has started.27,28 Approximately 1 to 2% of patients receiving unfractionated heparin will experience a fall in platelet count to less than the normal range or a 50% fall in the platelet count within the normal range. In the majority of cases, this mild to moderate thrombocytopenia appears to be a direct effect of heparin on platelets and is of no consequence. However, approximately 0.1 to 0.2% of patients receiving heparin develop an immune thrombocytopenia mediated by IgG antibody directed against a complex of PF4 and heparin.29 In some cases neutrophil acting peptide 2 (NAP-2) and inter-leukin 8 (IL8) also play a role in pathogenesis.
The incidence of heparin-induced thrombocytopenia (HIT) is lower with the use of LMWH;28,30 however, the clinical manifestations may be as or more severe than those seen with UFH.31 Furthermore, the nadir of the platelet count, onset, and duration of thrombocytopenia have been shown to be somewhat different.32 Recently, delayed onset of HIT has been described with the onset being as long as several weeks after the end of exposure to heparin, thus, making this syndrome sometimes more difficult to diag-nose.33 Furthermore, the incidence and severity of HIT varies among different patient populations being more prevalent in patients having cardiac or orthopedic procedures than for medical patients.34 The development of thrombocytopenia may be accompanied by arterial or DVT, which may lead to serious consequences such as death or limb amputation.27,34
When a clinical diagnosis of HIT is made heparin in all forms must be stopped immediately. In most centers the confirmatory laboratory test is an ELISA assay for the PF4-heparin complex, but, where possible, this should be confirmed with a functional assay, such as the serotonin release assay.34 In those patients requiring ongoing anticoagulation, an alternative form of anticoagulation must be undertaken immediately because of the high incidence of thrombosis when heparin is stopped.35 Some authorities recommend the use of alternative anticoagulants in all patients once a diagnosis is made. The most common alternative agents are the specific antithrombin argatroban34,35,36 or the direct thrombin inhibitor lepirudin.35,38,39 Both agents are given by intravenous infusion. Lepirudin has the advantage that it can be given to patients with renal insufficiency,34,35 but it has the disadvantage that with prolonged use antibodies develop and some of these can have serious deleterious effects, including anaphylaxis.40,41,42 Argatroban is primarily excreted by the kidney so that it cannot be used in people with severe renal failure but it can be used in patients with significant hepatic insufficiency.34,35,36 Both agents can be used in conjunction with vitamin K antagonists but it should be noted that argatroban by itself increases the INR beyond that observed with warfarin alone and this must be taken into account in controlling the vitamin K antagonist.37 The alternative antithrombotic agents should be continued until the platelet count is at least back to 100 x 109/L and/or the INR is therapeutic for two consecutive days.34 Danaparoid has been used in the past but is no longer available for many countries. The pentasaccharide fondaparinux has been used as an alternative antithrombotic agent in HIT patients and it has the advantage that it is given by a once daily subcutaneous injection.43,44 Insertion of an inferior vena cava filter is seldom indicated.
Osteoporosis has been reported in patients receiving unfractionated heparin in dosages of 20,000 U/day (or more) for more than six months.12 Demineralization can progress to the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible.12 Laboratory and clinical studies indicate that the incidence of osteoporosis with use of long-term LMWH is low.12
LOW-MOLECULAR-WEIGHT HEPARIN (LMWH) FOR THE INITIAL TREATMENT OF VTE
Heparin currently in use clinically is polydispersed unmodified heparin, with a mean molecular weight ranging from 10 to 16 kDa. Low molecular weight derivatives of commercial heparin have been prepared that have a mean molecular weight of 4-5 kDa.45,46
The LMWHs commercially available are made by different processes (such as nitrous acid, alkaline, or enzymatic depolymerization) and they differ chemically and pharma-cokinetically.45,46 The clinical significance of these differences, however, is unclear, and there have been very few studies comparing different LMWHs with respect to clinical outcomes.46 The doses of the different LMWHs have been established empirically and are not necessarily interchangeable. Therefore, at this time, the effectiveness and safety of each of the LMWHs must be tested separately.46
The LMWHs differ from unfractionated heparin in numerous ways. Of particular importance are the following: increased bioavailability (>90% after subcutaneous injection), prolonged half-life and predictable clearance enabling once- or twice-daily injection, and predictable antithrom-botic response based on body weight permitting treatment without laboratory monitoring.12,45,46 Other possible advantages are their ability to inactivate platelet-bound factor Xa, resistance to inhibition by platelet factor IV and their decreased effect on platelet function and vascular permeability (possibly accounting for less hemorrhagic effects at comparable antithrombotic doses).
There has been a hope that the LMWHs will have fewer serious complications such as bleeding, heparin-induced thrombocytopenia and osteopenia, when compared with unfractionated heparin.45,47 Evidence is accumulating that these complications are indeed less serious and less frequent with the use of LMWH. LMWH has been approved for the prevention and treatment of venous thromboembolism in pregnancy. These drugs do not cross the placenta and large case series suggest they may be both effective and safe. The LMWHs all cross-react with unfractionated heparin; therefore they cannot be used as alternative therapy in patients who develop heparin-induced thrombocytopenia. The hepa-rinoid danaparoid possesses a 10 to 20% cross-reactivity with heparin and it can be used safely in patients who have no cross-reactivity.
Four LMWHs are approved for clinical use in Canada, and three LMWHs have been approved for use in the United States.
In a number of early clinical trials (some of which were dose-finding), LMWH given by subcutaneous or intravenous injection was compared with continuous intravenous unfractionated heparin with repeat venography at day 7 to 10 being the primary endpoint.12 These studies demonstrated that LMWH was at least as effective as unfractionated heparin in preventing extension or increasing resolution of thrombi on repeat venography.
Subcutaneous unmonitored LMWH has been compared with continuous intravenous heparin in a number of clinical trials for the treatment of proximal DVT using long-term follow-up as an outcome measure.48-51,55-57 These studies have shown that LMWH is at least as effective and safe as unfractionated heparin in the treatment of proximal DVT. Pooling of the most methodologically sound studies suggests a significant advantage for LMWH in the reduction of major bleeding and mortality.52,53 Further recent studies have indicated that LMWH used predominantly out-of-hospital was as effective and safe as intravenous unfractionated heparin given in-hospital.55-57 Two clinical trials showed that LMWH was as effective as intravenous heparin in the treatment of patients presenting with PE.54,58 Economic analysis of treatment with LMWH versus intravenous heparin demonstrated that LMWH was cost-effective for treatment inhospital as well as out-of-hospital.59 As these agents have become more widely available for treatment, they have replaced intravenous unfractionated heparin in the initial management of patients with VTE.
Long-term LMWH has been compared with warfarin therapy in patients presenting with proximal DVT.60 Although these studies differ in design and doses of LMWH, they do indicate that LMWH is a useful alternative to warfarin therapy, particularly in patients who have recurrence of VTE while on therapeutic doses of warfarin (e.g., in the cancer population).60 More recently long-term low-molecular-weight heparin has been compared with long-term vitamin K antagonists for the treatment of a broad spectrum of patients and patients presenting with cancer and proximal DVT.61,62 In the latter study there was a significant decrease in the incidence of recurrent VTE with the use of long-term LMWH62 and in the former study involving a broad spectrum of patients including those with cancer, there was a significant decrease in the incidence of bleeding complica-tions.62 Based on these trials, LMWH has been recommended for a period of at least three to six months for patients presenting with VTE or PE and cancer.4
ANTICOAGULANT THERAPY: WARFARINS AND RELATED COMPOUNDS (VITAMIN K ANTAGONISTS)
Warfarin and related compounds have been shown to be efficacious and safe in a wide variety of clinical thrombotic disorders including venous thromboembolism, stroke prevention in nonvalvular atrial fibrillation, and prevention of systemic emboli in patients who have myocardial infarction or prosthetic heart valves. Although low-molecular-weight heparin has been shown to be efficacious and safe in the long-term treatment of venous thromboembolism particularly in patients with cancer, wafarin and related vitamin K antagonists remain the treatment of choice for the long-term treatment of venous thromboembolism.
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