Danaparoid

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Abstract
Danaparoid (danaparoid sodium) is a low molecular weight heparinoid which has undergone clinical study for use as continued anticoagulant therapy in patients with heparin-induced thrombocytopenia (HIT), for the prophylaxis and treatment of deep vein thrombosis (DVT), and for the treatment of disseminated intravascular coagulation (DIC). A nonblind study in patients with HIT has reported that complete clinical resolution is significantly more likely in patients receiving danaparoid than in patients receiving dextran 70. In addition, retrospective analyses and non-comparative data support the use of danaparoid for continued anticoagulant therapy in patients with HIT. Studies in patients undergoing hip surgery have shown that danaparoid significantly reduces the incidence of postoperative DVT compared with aspirin, warfarin, dextran 70 and heparin-dihydroergotamine, while additional data suggest no difference between danaparoid, enoxaparin and dalteparin. In patients undergoing abdominal or thoracic surgery for removal of a malignancy, danaparoid reduced the incidence of postoperative DVT compared with placebo, but showed no significant difference when compared with unfractionated heparin (UFH). Two studies have compared danaparoid with UFH in the prophylaxis of DVT following acute ischaemic stroke; twice daily danaparoid was significantly superior to UFH whereas there was no significant difference between a once-daily dosage and UFH. Danaparoid did not differ from UFH in terms of efficacy in the treatment of existing DVT. In all comparative studies examining the efficacy of danaparoid in the prophylaxis or treatment of DVT (versus warfarin, dextran 70, enoxaparin, dalteparin, aspirin, heparin-dihydroergotamine, UFH and placebo), the incidence of haemorrhagic complications did not differ between treatment groups. In patients with DIC, 61.9% of those patients receiving danaparoid experienced either disappearance or reduction of symptoms of DIC whereas 62% of those receiving UFH showed either no change or aggravation of their symptoms. There was no significant difference between treatment groups in tolerability or overall improvement of DIC. Conclusions: Danaparoid is an effective anticoagulant agent which has undergone clinical evaluation in a wide range of disease indications. Current guidelines support the use of danaparoid in prophylaxis of DVT following ischaemic stroke, and in patients who develop HIT. Danaparoid has shown efficacy in DIC, and for DVT prophylaxis in patients undergoing hip surgery although further data are required to establish the role of danaparoid in these indications. In particular, double-blind trials comparing danaparoid with such recommended therapies as the low molecular weight heparins will provide more definitive data on the place of danaparoid in the clinical management of these conditions and ultimately lead to improved patient outcomes. Danaparoid (danaparoid sodium) is a low molecular weight heparinoid, consisting of glycosaminoglycans, with a mean molecular mass of approximately 5500D. Its active components are heparan sulphate (≈84%), dermatan sulphate (≈12%) and chondroitin sulphates A and C (≈4%). Danaparoid catalyses the antithrombin-mediated inactivation of factor Xa leading to an inhibition of thrombin generation and ultimately thrombus formation. Danaparoid also weakly enhances antithrombin III and heparin cofactor II inactivation of factor IIa and has relatively little effect on platelet aggregation. There are no specific assays for determining the plasma concentrations of danaparoid and so pharmacokinetic measurements are based on the kinetics of its anticoagulant activities, primarily plasma antifactor Xa. The majority of data concerning danaparoid anticoagulant activities have been obtained following single-dose injections in healthy volunteers. The absolute bioavailability of danaparoid following subcutaneous injection approaches 100% and peak antifactor Xa activity occurs between 2 and 5 hours after administration. After intravenous administration, danaparoid has a mean distribution half-life of antifactor Xa activity of 2.34 hours. Renal excretion is the main route of elimination, accounting for up to 50% of the total plasma clearance of antifactor Xa activity. No clinically significant drug interactions have been reported between danaparoid and agents which act on platelet function or haemostasis. Oral chlorthalidone significantly increased the volume of distribution (Vd) of antifactor IIa activity, and decreased clearance (CL) and Vd of antifactor Xa activity. Digoxin significantly increased CL of antifactor Xa activity. Treatment of Heparin-induced Thrombocytopenia A small nonblind prospective study has compared danaparoid with dextran 70 as anticoagulant therapy in patients with heparin-induced thrombocytopenia (HIT). Patients randomised to danaparoid received a bolus intravenous injection of 2400U, followed by continuous intravenous infusion. Dextran 70 was given as an intravenous infusion of 1L on day 1, followed by infusions of 0.5L daily for the next 4 days. All patients also received concomitant warfarin. Study drugs were started within 24 hours of stopping unfractionated heparin (UFH) and were continued for at least 72 hours. Thrombocytopenia resolved in 23 patients receiving danaparoid (92%) and 15 patients receiving dextran 70 (88%) and the mean time to resolution of HIT did not differ between treatments (6.7 vs 7.3 days). Complete clinical resolution of thromboembolic events and partial or complete clinical recovery was significantly more likely in patients receiving danaparoid than in those receiving dextran 70. A retrospective analysis comparing patients receiving lepirudin as part of a formal clinical trial with patients receiving danaparoid in a general clinical setting has shown no significant difference between the treatments. In 730 patients with HIT receiving danaparoid in three noncomparative studies, thrombocytopenia persisted or appeared de novo in 6.1, 6.5 and 13.6% of patients. Several case reports and a series of 47 patients also document the successful use of danaparoid in the treatment of HIT in pregnant women, paediatric patients and patients undergoing cardiovascular surgery including cardiopulmonary bypass. Prophylaxis and Treatment of Deep Vein Thrombosis Six comparative studies have examined the use of danaparoid for the prophylaxis of deep vein thrombosis (DVT) in patients undergoing hip surgery (either fracture or hip replacement). Danaparoid was variously administered prior to surgery and then following surgery at a dosage of 750U subcutaneously twice daily. Two large, randomised studies showed that patients receiving danaparoid for 7 to 8 days following surgery developed significantly lower rates of DVT than patients receiving warfarin (patients with hip fracture 7 vs 21%; those with total hip replacement 14.6 vs 26.9%). Similarly, in a double-blind study in patients undergoing surgery for hip fracture, danaparoid was significantly more effective at reducing the incidence of DVT than aspirin (100mg twice daily) after treatment for 14 days following surgery (27.8 vs 44.3%). Randomised comparisons with dextran 70 and with heparin-dihydroergotamine (DHE) also suggest that danaparoid provides effective prophylaxis of DVT. The incidence of DVT in patients receiving danaparoid was significantly lower than in those receiving dextran 70 (10 vs 31%) or heparin-DHE(17 vs 33%). Finally, in a comparison of danaparoid with enoxaparin (40 mg/day subcutaneously) and dalteparin (5000 U/day subcutaneously) in patients undergoing surgery for hip fracture, there was no significant difference in the incidence of DVT between treatment groups (5.7 vs 15.4 vs 8.8%, respectively). Danaparoid has also been compared with UFH for the prophylaxis of DVT in 490 patients undergoing surgery for suspected gastrointestinal malignancy or lung cancer. There was no statistically significant difference in the frequency of positive leg scan results between treatment groups (danaparoid 7.9 vs UFH 11.2%). In two double-blind studies in patients with ischaemic stroke, no significant difference was observed between danaparoid (1250U once daily) and UFH (5000 U/day subcutaneously twice daily) in reducing the incidence of DVT (14.6 vs 19.8%) with treatment for a minimum of 9 days. However, in a separate study, danaparoid (750U twice daily) was significantly more effective than UFH (5000 U/day subcutaneously twice daily) in reducing the occurrence of DVT (9 vs 31%) when treatment was continued for 14 days. In a placebo-controlled, double-blind study, danaparoid (750U twice daily) significantly reduced the incidence of DVT compared with placebo (4 vs 28%). The ‘Trial of ORG 10172 (danaparoid) in Acute Stroke Treatment’ (TOAST) was a multicentre, placebo-controlled study in 1275 patients with acute or progressing ischaemic stroke to assess the effect of danaparoid on neurological outcomes. There was no significant difference in the frequency of favourable outcome (assessed using the Glasgow Outcome Scale and Barthel Index) at 7 days or at 3 months. There was also no significant difference between treatment groups in the frequency of very favourable outcome at 3 months; however, after 7 days’ treatment, significantly more patients receiving danaparoid reported very favourable outcomes compared with those receiving placebo. The incidence of DVT during the 3-month follow-up was significantly lower in patients who received danaparoid than in patients who received placebo. An assessor blind study has compared the efficacy of danaparoid with that of UFH for the treatment of venous thromboembolism in 188 patients. The frequency of recurrence or extension of DVT was significantly lower in patients receiving danaparoid 2000U subcutaneously twice daily (13%) than in those receiving UFH (28%) or in those receiving danaparoid 1250U subcutaneously twice daily (28%) when assessed after 5 to 8 days. Similar results were found 2 months after the initiation of study treatment. Treatment of Disseminated Intravascular Coagulation The use of danaparoid (1250U twice daily) in the treatment of disseminated intravascular coagulation (DIC) was examined in 85 patients in a randomised double-blind, double-dummy comparison with UFH (continuous intravenous infusion of 7 to 10 U/kg/h). There was no significant difference in the rate of change of the underlying condition between treatment groups after 5 days of treatment. Ten patients receiving danaparoid (23.3%) and 12 patients receiving UFH (28.6%) were considered to have an easing or recovery of their underlying condition. Similar numbers of patients in each group showed no change in (55.8 and 47.6%) or aggravation of (20.9 and 23.8%) the severity of their underlying condition. There was also no difference between treatment groups in DIC scores during the study. The only comparative study with danaparoid in the treatment of DIC has reported that 61.9% of patients receiving danaparoid experienced either disappearance or reduction of symptoms of DIC whereas 62% of patients receiving UFH showed either no change or aggravation of their symptoms. Heparin-Induced Thrombocytopenia A noncomparative study has reported that from a total of 667 patients who were receiving danaparoid for antithrombotic medication with associated HIT, 67 developed serious adverse events (including new or extension of thrombosis, skin rash, bleeding, and persistent of recurrent platelet count). Indirect comparison of danaparoid and lepirudin suggests that significantly fewer patients receiving danaparoid developed a major bleeding event than patients receiving lepirudin (2.5 vs 10.4%). Finally, in a prospective nonblind comparative study, one patient receiving danaparoid and three receiving dextran 70 died of HIT-associated thrombosis. Deep Vein Thrombosis In 9 studies which evaluated the efficacy and tolerability of danaparoid in the prophylaxis of DVT following surgery, the incidence of haemorrhagic complications did not differ significantly between danaparoid and the comparator agent. Most studies showed no significant difference between danaparoid and the comparator agent regarding blood loss and transfusion requirements during surgery; however, one study reported that significantly fewer patients receiving danaparoid required a postoperative blood transfusion compared with those receiving dextran 70 and, in a second study, more patients receiving danaparoid required intraoperative blood transfusion compared to those receiving heparin-DHE. Blood loss and mortality were generally similar between treatment groups. In the TOAST study, major bleeding events were significantly more frequent in patients receiving danaparoid during prophylaxis (7 days), within 10 days of starting therapy and throughout the 3-month period of observation than in those receiving placebo (p < 0.05 in all cases). In addition, serious brain bleeding during the initial 10 days of therapy, and minor bleeding during treatment and during the initial 10 days of therapy were also observed significantly more frequently in patients receiving danaparoid than in those receiving placebo (p < 0.05 in each case). Five patients with ischaemic strokes from three studies developed major bleeding complications; three of these patients were receiving danaparoid, one was receiving UFH, and one placebo. One case of a fatal haemorrhagic transformation associated with danaparoid treatment was reported. In patients receiving danaparoid for treatment of DVT, major bleeding occurred in two patients receiving UFH and two receiving danaparoid. Disseminated Intravascular Coagulation Data from the only comparative study with danaparoid in the treatment of DIC suggests that there are no significant tolerability differences between danaparoid and UFH. Three patients receiving UFH and no patients receiving danaparoid experienced bleeding-related adverse events. Throughout Western Europe danaparoid is approved for the treatment of HIT. For continued anticoagulation in patients with HIT, danaparoid should be administered intravenously as abolus of 2500U (1250U if bodyweight is 90kg) followed by a continuous intravenous infusion of 400 U/h for 2 hours, 300 U/h for the next 2 hours, then a maintenance infusion of 200 U/h for 5 days. In the US, danaparoid has received regulatory approval for the prophylaxis of postoperative DVT in patients undergoing elective hip replacement. In Europe, it has received regulatory approval for the prophylaxis of DVT in patients undergoing general or orthopaedic surgery. For DVT prophylaxis, danaparoid should be administered by subcutaneous injection at a dose of 750U twice daily beginning 1 to 4 hours before surgery and then not sooner than 2 hours after surgery. Treatment duration should be 7 to 10 days, and up to 14 days where necessary. In Japan, danaparoid has received regulatory approval for use in the treatment of DIC. The recommended normal adult dosage is 1250U twice daily via intravenous administration. Patients with moderately or severely impaired kidney or liver function, or impaired haemostasis should exercise caution when taking danaparoid, as delayed excretion may lead to haemorrhage. Dosage should be reduced or intervals between dosages increased if serum creatinine levels are ≥2 g/L. In patients with severe renal damage, consideration should be given to suspending treatment. Breast-feeding mothers should only be given danaparoid if clearly required, and the tolerability of danaparoid in infants and paediatric patients has not been confirmed. Finally, danaparoid is contraindicated in patients with haemorrhage (or at risk of haemorrhage), requiring haemodialysis, with severe liver damage, with hypersensitivity to danaparoid, with HIT who display cross-reactivity between danaparoid and HIT antibodies, with diabetic retinopathy and in those who have recently undergone brain, spinal or eye surgery.