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Tinzaparin

A Review of its Pharmacology and Clinical Potential in the Prevention and Treatment of Thromboembolic Disorders

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Summary

Synopsis

Tinzaparin, a low molecular weight (LMW) heparin with an average molecular weight of 4.5 ± 1.5kD, has greater bioavailability and a longer duration of action than unfractionated heparin, allowing it to be administered once daily by subcutaneous injection for both prophylaxis and treatment of deep venous thrombosis (DVT). Like other members of its class, tinzaparin has a greater ratio of anti-factor Xa/anti- f actor IIa activity than unfractionated heparin, providing the theoretical advantage of similar antithrombotic efficacy with a diminished risk of haemorrhagic complications.

In a small number of clinical trials, tinzaparin was found to be more effective than intravenous dextran or oral warfarin sodium as prophylaxis against DVT in high-risk patients undergoing orthopaedic surgery, and more effective than subcutaneous heparin in both general surgical patients and medical patients with an immobilising illness. When used for the treatment of established DVT, tinzaparin was more effective in preventing DVT recurrence than intravenous heparin, both initially and during a 3- month follow-up period when patients received warfarin sodium. Tinzaparin was also used successfully in one small study to maintain the patency of haemodialysis circuits over a 6- month period, with favourable effects on the lipid profile of such patients.

Tinzaparin is well tolerated, the most frequent complication being injection site haematoma. In comparative trials, tinzaparin was associated with fewer major haemorrhagic complications than intravenous heparin (when used for treatment of venous thrombosis), but more than warfarin sodium. Other adverse events which have been reported in tinzaparin-treated patients include elevated liver enzyme levels and thrombocytopenia.

Thus, although clinical experience is limited at present, available data suggest that, in common with other LMW heparins, tinzaparin is likely to prove an effective alternative to unfractionated heparin for both the prevention and treatment of DVT, with the advantage of more convenient administration and decreased monitoring requirements.

Pharmacodynamic Properties

Tinzaparin is a low molecular weight (LMW) heparin formed by enzymatic depolymerisation of heparin. It has an average molecular weight of 4.5 ± 1.5kD. Its anti-factor Xa activity is 75 IU/mg and anti-factor IIa activity 50 IU/mg, with reference to the First International Standard for LMW heparins. LMW heparins vary in their content and structure and relative proportions of high and low molecular weight heparin molecules. These differences result in differing anti-factor Xa and anti-factor IIa activities and probably explain the differing antithrombotic, haemorrhagic and pharmacokinetic profiles observed in clinical practice. In common with other LMW heparins, tinzaparin has a greater anti-factor Xa/anti-factor IIa activity ratio than unfractionated heparin, and a less marked effect than heparin on thrombus formation in animal models. Tinzaparin demonstrated reduced activity relative to heparin in delaying production of thrombi ex vivo in blood samples from volunteers. LMW heparins may increase transport of lipoprotein lipase from extrahepatic sites to the liver, and tinzaparin was reported to have a beneficial effect on the lipid profile when substituted for heparin in patients undergoing haemodialysis. In common with other LMW heparins, tinzaparin has a lesser effect on platelet activation and is also less affected by platelet factor 4 than heparin. It also appears to act synergistically with tissue factor pathway inhibitor.

Unlike that of heparin, the anti-factor Xa activity of tinzaparin cannot be fully neutralised by a single dose of protamine sulfate, as observed with other LMW heparins.

Pharmacokinetic Properties

As with other LMW heparins, the pharmacokinetic properties of tinzaparin have been determined indirectly by measurement of anti-factor Xa and anti-factor IIa activities in plasma. Following subcutaneous injection, peak plasma anti-factor Xa and anti-factor IIa activities are reached after approximately 4 to 6 hours and are dose dependent within the range of tinzaparin doses in clinical use. The overall bioavailability, based on anti-factor Xa and anti-factor IIa activity, respectively, is 90% and 67%.

Peak plasma anti-factor Xa activity progressively increases when tinzaparin is administered for several days, but trough levels essentially return to baseline, indicating the absence of accumulation. The apparent volume of distribution is 3.9L for anti-factor Xa activity and 10.1L for anti-factor IIa activity. Tinzaparin does not cross the placenta during the second trimester of pregnancy, but otherwise the pattern and extent of tissue distribution in humans has not been reported.

Unlike that of heparin, the elimination of tinzaparin and other LMW heparins appears to occur primarily by an unsaturable renal mechanism. Data in humans are not available, but studies in the dog have shown that 80 to 90% of administered tinzaparin is recovered in the urine and 1 to 2% in the faeces. The elimination half-life of anti-factor Xa activity in volunteers after subcutaneous administration of tinzaparin was 82 minutes. The effects of renal or hepatic disease on the pharmacokinetics of tinzaparin are unknown.

Therapeutic Trials

In a small number of clinical trials, subcutaneous tinzaparin, administered once daily, was found to reduce the incidence of deep venous thrombosis (DVT) in both surgical and medical patients. In patients undergoing hip surgery, tinzaparin 50 IUaXa/kg/day was significantly more effective than placebo when used in conjunction with early mobilisation (4 days after surgery) and more effective than intravenous dextran (incidence of DVT 17.1 vs 28.7%). In a comparative study involving 1436 patients, tinzaparin 75 IUaXa/kg was of similar efficacy to oral warfarin in patients undergoing hip surgery, and more effective than warfarin in those undergoing knee surgery, although a high incidence of DVT was noted with both regimens in the latter setting (incidence of DVT 45 vs 54.9%). Tinzaparin was associated with more major haemorrhagic complications (2.8 vs 1.2% of patients) and wound haematomas (6.7 vs 3.6%) than warfarin.

In patients undergoing general surgery, tinzaparin 3500 IUaXa or 50 IUaXa/kg per day was reported to be effective in decreasing the incidence of DVT and tinzaparin 3500 IUaXa daily was shown to be equivalent to standard treatment with subcutaneous unfractionated heparin (5000IU twice daily) in patients with specific risk factors for developing DVT (incidence of DVT 2.6 vs 3.5%).

In a single study in medical patients at risk of developing DVT because of immobilising spinal cord injury, tinzaparin (3500 IUaXa daily) was more effective than heparin (5000IU 3 times daily) and tended to produce less bleeding when administered over an 8-week period.

Tinzaparin 150 or 175 IUaXa/kg/day was reported to prevent progression or recurrence of established DVT in 2 studies and the higher dose was more effective than intravenous adjusted-dose heparin, both in the immediate treatment period and during a 3-month follow-up period when patients had been switched to oral warfarin (2.8 vs 6.9% of patients). Furthermore, tinzaparin was associated with less major bleeding than heparin during initial treatment.

When substituted for heparin to maintain the patency of haemodialysis lines, tinzaparin 40 IUaXa/kg was shown in one small trial to have possible advantages over heparin with respect to its effects on lipoproteins.

Tolerability

Haemorrhagic complications with tinzaparin have not been a major problem in clinical trials to date. Although both blood loss and transfusion requirements were higher relative to placebo in patients undergoing hip surgery, none of the findings were considered to be clinically important. In a small number of comparative trials, tinzaparin was associated with a similar incidence of haemorrhagic complications to subcutaneous heparin or intravenous dextran, but more than warfarin sodium. Larger doses of tinzaparin (175 IUaXa/kg daily) used for treatment of established DVT produced significantly fewer haemorrhagic complications than did intravenous heparin (0.5 vs 5.0% of patients) during initial treatment, although delayed bleeding during long term follow up (after patients were switched to oral warfarin) was more common in tinzaparin recipients.

The most common adverse event during tinzaparin treatment has been the development of haematomas at the injection site. These appeared to be dose related, occurring in 1.2% of patients receiving tinzaparin 2500 IUaXa daily, 4.9% of patients receiving 3500 IUaXa daily and up to 80% of patients receiving 150 IUaXa/kg daily. Haematomas occurring with the largest dose of tinzaparin rarely exceeded lcm in diameter and in no case did a local haematoma require discontinuation of treatment.

Thrombocytopenia was reported in approximately 2% of patients in 2 studies. Transient increases in aspartate aminotransferase and alkaline phosphatase activities were reported in 35% and 16.5% of patients, respectively, receiving 50 IUaXa/kg tinzaparin as prophylaxis in hip replacement surgery.

Dosage and Administration

For the prevention of DVT in high-risk surgical patients, the usual dose of tinzaparin is 50 IUaXa/kg body weight, administered subcutaneously 2 hours prior to surgery, then daily for 7 to 10 days. Patients at moderate risk of developing DVT may receive 3500 IUaXa. A daily dose of 175 IUaXa/kg tinzaparin, commenced as soon as possible after diagnosis and continued until stabilisation of warfarin therapy, has proved effective in the treatment of established DVT.

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    Heather A. Friedel & Julia A. Balfour

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Various sections of the manuscript reviewed by: T. Akiba, Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan; J.F Cade, Intensive Care Department, Royal Melbourne Hospital, Melbourne, Victoria, Australia; D. Green, Northwestern University Atherosclerosis Program, Rehabilitation Institute of Chicago, Chicago, Illinois, USA; J. Hirsh, Hamilton Civic Hospitals Research Centre, Henderson Hospital, Hamilton, Ontario, Canada; R.D. Hull, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; T. Mätzsch, Department of Surgery, University of Lund, Malmö General Hospital, Malmö, Sweden; E.A. Ofosu, Department of Pathology, McMaster University, Hamilton, Ontario, Canada; M. Verstraete, Center for Molecular and Vascular Biology, Catholic University of Leuven, Leuven, Belgium.

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Friedel, H.A., Balfour, J.A. Tinzaparin. Drugs 48, 638–660 (1994). https://doi.org/10.2165/00003495-199448040-00010

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