Published in:
01-07-2001 | Adis Drug Evaluation
Reviparin
A Review of its Efficacy in the Prevention and Treatment of Venous Thromboembolism
Published in: Drugs | Issue 8/2001
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Abstract
Reviparin (reviparin sodium) is a low molecular weight heparin (LMWH) that catalyses the inactivation of factors Xa and IIa by binding to antithrombin, which ultimately leads to the inhibition of the clotting cascade. It is administered subcutaneously.
Reviparin 7000 to 12 600 anti-XalU/day was found to be as effective as intravenous unfractionated heparin in preventing the clinical recurrence of acute deep vein thrombosis (DVT) and/or pulmonary embolism in 1 large randomised, multi-centre trial (COLUMBUS) and was significantly more effective than intravenous unfractionated heparin in the prevention of recurrent venous thromboembolism in another large randomised, multicentre trial (CORTES). Reviparin has also been compared with unfractionated heparin in children with established DVT. However, the trial was under-powered and no conclusion could be made regarding comparative efficacy.
As prophylaxis, reviparin 1750 anti-XalU once daily was as effective as unfractionated heparin 5000IU twice daily in 1311 patients undergoing abdominal surgery and, in a once daily dosage of 4200 anti-XalU, was as effective as subcutaneous enoxaparin sodium 40 mg/day or acenocoumarol in patients undergoing hip replacement surgery. Reviparin 1750 anti-XalU also effectively prevented DVT, compared with no treatment, in patients undergoing knee arthroscopy. It was also more effective than placebo in patients with brace immobilisation of the lower extremity. Reviparin was compared with ’standard care’ in children with central venous lines. However, the trial was too small to make conclusions regarding its efficacy.
Comparative data indicate that reviparin is at least as well tolerated as heparin and enoxaparin sodium. However, in a large (n = 1279) trial there were significantly fewer major bleeding episodes in patients receiving reviparin than in patients given the oral anticoagulant acenocoumarol. The most commonly reported adverse events in therapeutic trials have been intraoperative blood loss and postoperative bleeding complications such as wound haematoma, bruising and injection site haemorrhage. Reviparin was also well tolerated in 2 studies in children aged ≤16 years.
Conclusion: Reviparin has shown efficacy in the treatment of established DVT and in the prevention of postoperative DVT after moderate and high risk surgery and was as effective as enoxaparin sodium or acenocoumarol in patients undergoing hip replacement surgery. As an effective and well tolerated antithrombotic agent, reviparin is likely to assume a significant role in the treatment and prevention of DVT, as it appears to have a preferable tolerability profile to subcutaneous heparin after moderate risk surgery and is at least as effective as intravenous heparin in the treatment of established DVT.
Pharmacodynamic Properties
Reviparin (reviparin sodium), a low molecular weight heparin (LMWH) manufactured by cleavage of unfractionated heparin (hereinafter referred to as heparin) with nitrous acid and subsequent Chromatographic purification, has a mean molecular weight of 4400D and a mean peak molecular weight of 3900D. Reviparin catalyses the inactivation of factors Xa and IIa by binding to antithrombin, which ultimately leads to the inhibition of the clotting cascade. However, in addition to a direct effect, the drug’s actions may be modulated by other factors such as tissue factor pathway inhibitor (TFPI). Preclinical and clinical studies have shown that reviparin, like other LMWHs and heparin, stimulates the release of TFPI from endothelial cells, thereby increasing the rate of inactivation of factor Xa and the thromboplastin-factor VIIa complex.
Reviparin has a higher anti-Xa/IIa ratio than heparin and the anti-Xa activity appears to last longer: anti-Xa activity in rabbits dissipated within 2 to 3 hours after intravenous administration of heparin compared with >6 hours after reviparin. After subcutaneous administration of reviparin 40 to 80 anti-XaIU/kg in 10 healthy volunteers, anti-Xa activity increased gradually, reaching a peak after 90 to 150 minutes, before returning to baseline levels within 6 to 8 hours.
Intravenous reviparin produced dose-dependent antithrombotic and anticoagulant effects in a rabbit model of stasis thrombosis. The anticoagulant activity of heparin is conventionally measured using the activated partial thromboplastin time (aPTT), a measure of the intrinsic pathway of blood coagulation. However, unlike heparin, reviparin has minimal effects on the aPTT at prophylactic or therapeutic doses. Therefore, aPTT measurement is not useful for monitoring reviparin.
Reviparin produced a dose-dependent increase in blood loss at dosages that were proportionally higher than those used to assess the antithrombotic actions of the drug after both intravenous and subcutaneous administration in a rabbit ear blood loss model.
Coadministration of oral aspirin 300mg with subcutaneous reviparin (6300 anti-XalU) for 3 days in 9 healthy volunteers significantly prolonged the bleeding time compared with reviparin alone, although this was not thought to be clinically significant.
In a study in 12 healthy volunteers, protamine chloride (given in a 1: 2 ratio with reviparin and 1.2: 1 ratio with heparin) completely neutralised the anti-Xa activity of heparin but reduced the anti-Xa activity of reviparin by only 20 to 40%.
Pharmacokinetic Profile
The pharmacokinetic profile of reviparin administered subcutaneously is characterised by rapid absorption, high bioavailability (≥90%), slow elimination [half life (t1/2β) of 2.5 to 4.3 hours) and dose-independent clearance (⁈1.2 L/h). Maximum plasma anti-Xa activity was reached within 2 to 3.5 hours irrespective of dose.
The area under the plasma anti-Xa activity-time curve (AUC0-24h) was significantly lower with reviparin than with enoxaparin sodium (2.44 vs 3 IU/ml · h, p < 0.05) after adjustment for in vitro anti-Xa activity.
In 10 patients with severe renal failure, t1/2β (5 vs 3.3 hours), mean residence time (8.6 vs 6.5 hours) and the apparent volume of distribution (0.13 vs 0.08 L/kg) of reviparin were significantly higher than those reported in 6 healthy volunteers. Elimination of the drug did not differ to a large extent between interdialysis (t1/2β = 5h) and dialysis periods when dialysis was conducted with high or low permeability membranes (t1/2β = 3.6 vs 4.7h). Mean pharmacokinetic parameters were unchanged in elderly patients.
In children aged 3 days to 16 years with central venous lines, the level of anti-Xa activity in patients weighing ≥5kg peaked (average 0.25 anti-XaIU/ml) 2 hours after administration of reviparin 30 anti-XaIU/kg twice daily. Patients weighing <5kg received reviparin 50 anti-XaIU/kg twice daily and the level of anti-Xa activity (average 0.27 anti-XaIU/ml) peaked 1 to 4 hours after treatment.
Therapeutic Efficacy
Treatment of Established Venous Thromboembolism In 1021 patients (the COLUMBUS trial) with acute symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) or both, fixed dose subcutaneous reviparin (7000 to 12 600 anti-XalU/day dose-adjusted according to 3 body-weight categories) was found to be as effective as adjusted dose intravenous heparin. Of the 510 patients receiving reviparin, 27 (5.3%) had episodes of documented recurrent venous thromboembolism over the 12-week period. Similarly, among the 511 patients treated with heparin, 25 (4.9%) had documented episodes. The majority of the recurrent venous thromboembolic and major bleeding events occurred during the first 14 days of treatment. There were no episodes of fatal bleeding during the trial but 3 patients from each treatment group, each of whom presented with PE, had fatal episodes of PE.
In contrast, results from the CORTES study show that subcutaneous reviparin (7000 to 12 600 anti-XalU/day dose-adjusted according to 3 bodyweight categories) was significantly more effective than intravenous heparin (dose-adjusted to achieve aPTT values between 1.5 and 2.5 times baseline) in preventing the clinical recurrence of DVT and/or PE (in patients with confirmed DVT). Significantly more patients in the reviparin twice daily (53.5%) and reviparin once daily (53.9%) groups experienced thrombus regression, compared with patients in the heparin group (40.8%).
Reviparin has been compared with heparin in the treatment of venous thromboembolism in children aged ≤16 years and >60 days in a randomised, nonblind (with blinded outcome assessment), multicentre trial. Among reviparin recipients, 2 of 37 (5.4%) had an episode of recurrent venous thromboembolism, compared with 5 of 41 (12.2%) patients who received heparin.
Prophylaxis of Venous Thromboembolism The efficacy of subcutaneous reviparin in the prevention of thromboembolism after surgery has been examined in a noncomparative dose-finding study, a comparison with no treatment (after knee arthroscopy) and in randomised, double-blind or single-blind comparisons with placebo, enoxaparin sodium, subcutaneous heparin or acenocoumarol. It has also been compared with “standard care” in the prevention of DVT in children aged ≤16 years with central venous lines in a randomised, nonblind (with blinded outcome assessment), multicentre study.
Reviparin 1750 anti-XalU was significantly more effective than placebo in the prevention of DVT in patients immobilised with a cast after lower extremity fracture or rupture of the Achilles tendon.
In a trial in 1311 patients undergoing abdominal surgery, reviparin 1750 anti-XalU administered 2 hours before surgery and once daily for ≥5 days after surgery was as effective as subcutaneous heparin 5000IU twice daily.
In high risk patients, preliminary dose-finding work showed that a once daily subcutaneous injection of reviparin 4200 anti-XaIU, initiated 10 to 12 hours before hip replacement surgery, completely prevented the development of postoperative DVT. Furthermore, in a large randomised, multicentre trial, a once daily subcutaneous dosage of reviparin 4200 anti-XalU was as effective as a once daily subcutaneous dosage of enoxaparin sodium 40mg in patients undergoing total hip replacement surgery. Additionally, in a large (n = 1279) study in patients after undergoing total hip replacement surgery, the cumulative failure rate of therapy (the combined incidence of a confirmed symptomatic thromboembolic event, a major bleed, or death) over the 6-week period after surgery was significantly in favour of reviparin compared with acenocoumarol (3.7% vs 8.3%, p = 0.001).
Reviparin also effectively prevented DVT in patients undergoing knee arthroscopy, compared with no treatment, in a randomised, nonblind (with blinded outcome assessment), single-centre trial. Among 117 patients randomised to receive reviparin 1750 anti-XalU/day, 1 (0.9%) developed DVT, compared with 5 (4.1%) patients who received no treatment. There was no incidence of PE in either group.
Reviparin was also effective in the prophylaxis of venous thromboembolism during pregnancy in patients with a history of venous thromboembolism.
In children aged ≤16 years with central venous lines, 11 of 78 (14.1%) reviparin recipients (30 anti-XaIU/kg twice daily) developed DVT compared with 10 of the 80 (12.5%) patients who received “standard care”. Three patients in each group had symptomatic DVT, and of the 7 patients aged between 0 and 3 months, 3 experienced DVT.
Tolerability
Clinical trials have shown that subcutaneous reviparin is well tolerated when used for the prophylaxis and treatment of thromboembolism. Comparative data indicate that its tolerability profile is at least as good as those of intravenous heparin and subcutaneous enoxaparin sodium. Furthermore, long term use of reviparin (≤6 weeks) was well tolerated in 2 studies.
In patients undergoing abdominal surgery, reviparin was associated with significantly fewer postoperative bleeding complications, such as wound haematoma, bruising and injection site haemorrhage, than heparin. However, there were no statistically significant between-group differences in episodes of peri- and postoperative blood loss or blood transfusion requirements.
In patients undergoing total hip replacement surgery, reviparin was associated with slightly fewer haematomas and bruisings than enoxaparin sodium, although the differences did not reach statistical significance. However, in a large (n = 1279) trial there were significantly fewer major bleeding episodes in patients receiving reviparin than in patients given the oral anticoagulant acenocoumarol. Furthermore, there were no episodes of major bleeding in 2621 immobilised outpatients who self-administered reviparin 1750 anti-XalU for 1 to 4 weeks; 4% of patients experienced injection site haemorrhage and minor bleeding events occurred in 9%.
In a small trial involving 158 children with central venous lines, no patients who received reviparin 30 anti-XaIU/kg twice daily for 30 days experienced major bleeding, compared with 1 patient who received “standard care”.
Bleeding complications tend to be less frequent in nonsurgical patients with established DVT than in surgical patients. There was no statistically significant difference between the number of episodes of major or minor bleeding in patients receiving reviparin or intravenous heparin.
As yet, there have been no reports of reviparin-induced osteoporosis. Limited data suggest the drug may be well tolerated during pregnancy but this has to be confirmed.
In a small trial involving 78 children with established venous thromboembolism, major bleeding complications occurred in 3 of 37 (8.1%) patients who received reviparin 100 anti-XaIU/kg twice daily for 3 months, compared 5 of 41 (12.2%) heparin recipients.
Dosage and Administration
Reviparin is approved for the prevention of DVT and PE in patients at moderate risk (i.e. general surgery) and high risk (i.e. orthopaedic surgery), for the treatment of venous thromboembolism and for anticoagulation during haemodialysis and extracorporeal circulation. The recommended injection site is in the skin of the abdominal wall, between the umbilicus and iliac crest, or on the front of the thigh. Because of the risk of provoking wound haematomas, reviparin should not be administered intramuscularly.
The recommended dosage for the prophylaxis of DVT in patients undergoing moderate risk surgery (i.e. abdominal surgery) is a subcutaneous injection of reviparin 0.25ml (1750 anti-XalU) initially administered 2 hours prior to surgery and continued once daily until the patient is fully mobile.
For high risk surgical patients (i.e. those undergoing orthopaedic surgery) a once daily subcutaneous injection of reviparin 0.6ml (4200 anti-XalU), initiated 12 hours before surgery, is recommended for the prophylaxis of DVT.
Treatment of established DVT involves a twice daily subcutaneous injection of reviparin, dose-adjusted according to 3 bodyweight categories, with concomitant treatment with an oral anticoagulant.
Prophylaxis or treatment with reviparin does not require the monitoring of aPTT values. However, in elderly patients and patients with renal insufficiency, monitoring of the anti-Xa levels is recommended because of possible delayed elimination of the drug. Anti-Xa monitoring in pregnant patients is also recommended because of the bodyweight increase over the course of the pregnancy.