, Volume 64, Issue 13, pp 1479-1502
Date: 17 Sep 2012

Tinzaparin Sodium

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Summary

Abstract

Tinzaparin sodium (tinzaparin; innohep®) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH).

In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH.

Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and homebased treatment with tinzaparin may offer greater cost benefits than hospitalbased therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.

Pharmacological Properties

Subcutaneous (SC) tinzaparin sodium (tinzaparin) increases anti-factor Xa and anti-factor IIa activities in plasma in a dose-related fashion. Tinzaparin stimulates the release of tissue factor pathway inhibitor, which contributes to the anticoagulant, and possibly the anti-tumour activities, of tinzaparin. Plasma antithrombin levels and platelet counts are not affected to a clinically significant extent by tinzaparin.

The absorption half-life of single-dose SC tinzaparin in terms of anti-factor Xa activity was 200–248 minutes in healthy volunteers, and the bioavailability of the drug is 87–90%. However, the pharmacokinetics of tinzaparin are subject to wide interindividual variability. Elimination is predominately by renal filtration. Clearance of tinzaparin may be reduced in patients with severe renal impairment. The pharmacokinetics of tinzaparin are not affected by bodyweight or body mass index when the drug is administered at 75 or 175 anti-Xa IU/kg.

Therapeutic Efficacy

Use in Thromboprophylaxis: Prophylactic dosages of SC tinzaparin were superior to placebo and intravenous (IV) dextran in the prevention of deep vein thrombosis (DVT) in patients undergoing total hip replacement. Efficacy tended to be greater with higher dosages of tinzaparin (approximately 75 anti-Xa IU/kg) than with lower dosages (approximately 50 anti-Xa IU/kg).

In a study of 1207 patients, SC tinzaparin 75 anti-Xa IU/kg once daily was of similar thromboprophylactic efficacy to adjusted-dosage oral warfarin when given for 14 days to patients undergoing total hip arthroplasty, but the incidence of DVT was significantly lower with tinzaparin than with warfarin in patients receiving knee replacement. Tinzaparin 4500 anti-Xa IU/day was of equivalent antithrombotic efficacy to enoxaparin sodium (enoxaparin) 40 mg/day; both low molecular weight heparins (LMWHs) were given as single daily SC injections in 440 patients undergoing total hip replacement.

Seven to ten days prophylaxis with SC tinzaparin 3500 anti-Xa IU once daily or SC unfractionated heparin (UFH) 5000IU twice daily was of equivalent efficacy and superior to tinzaparin 2500 anti-Xa IU once daily in a double-blind study in 1290 patients undergoing general surgery. Prolonged thromboprophylaxis with tinzaparin for up to an additional 28 days maintains, and may even improve on, short-term efficacy in terms of DVT reduction. The thromboprophylactic efficacy of tinzaparin has been further demonstrated in small studies in patients with motor paralysis.

Treatment of Established Venous Thromboembolic Disease: SC tinzaparin 175 anti-Xa IU/kg/day for approximately 5–7 days was at least as effective as adjusted-dosage IV UFH in the initial management of 432 patients with acute proximal DVT in one study, and in 812 patients with pulmonary embolism in two other studies. Preliminary data indicate that tinzaparin (175 anti-Xa IU/kg/day or dosage not stated) is as effective as SC dalteparin sodium (200 anti-Xa IU/kg/day) or long-term oral warfarin in the outpatient treatment of venous thromboembolism, and suggests that home treatment with an LMWH is well accepted by patients. Analyses of hospital costs from the perspective of healthcare or third party payers have indicated cost advantages with SC tinzaparin relative to IV adjusted-dosage UFH in the treatment of established thromboembolic disease. Costs may be further reduced with outpatient treatment with tinzaparin in this patient group.

Use in Haemodialysis: Tinzaparin was effective in the maintenance of patency of haemodialysis circuits, with additional benefits compared with UFH in terms of improvements in patients’ lipid metabolism, especially over the long term. Tinzaparin 3000–4500 anti-Xa IU was less effective than, or had similar efficacy to, IV adjusted-dose UFH in terms of clot formation in small crossover studies, although, in one study, the initial tinzaparin dose (3500 anti-Xa IU) was considered too low for sufficient anticoagulant effect. The anticoagulant efficacy of tinzaparin (mean 5024 anti-Xa IU/session) was similar to that of dalteparin (mean 5546 anti-Xa IU/session) in a randomised single-blind trial in 149 evaluable patients.

Tolerability

Major bleeding complications with SC tinzaparin are infrequent in clinical studies. There were no significant differences in incidence of postoperative bleeding between SC tinzaparin 2500 or 3500 anti-Xa IU daily or SC UFH 5000IU twice daily for thromboprophylaxis in 1290 patients (mean age 61 years) undergoing general surgery. In 1207 patients (mean age 66 years) undergoing orthopaedic surgery, rates of major bleeding over 14 days were 2.8% with SC tinzaparin 75 anti-Xa IU/kg/day and 1.2% with adjusted-dosage oral warfarin (p = 0.04). Incidences of major bleeding with SC tinzaparin 175 anti-Xa IU/kg once daily were either similar to or significantly lower (0.5% vs 5%; p = 0.006) than those with IV activated partial thromboplastin time-adjusted UFH in patients with established VTE, including elderly individuals. Tinzaparin was well tolerated in patients undergoing haemodialysis; during long-term maintenance, the incidence of major or minor bleeding was similar with tinzaparin (mean 5024 anti-Xa IU) to that with dalteparin (mean 5546 anti-Xa IU). In patients with renal insufficiency relative to those with normal renal function, the incidence of bleeding events with tinzaparin appeared lower than that with UFH. The incidence of major bleeding (1.5%) in 200 very elderly patients (mean age 85.2 years) receiving tinzaparin (initial dosage 175 anti-Xa IU/kg) in an observational study was similar to that reported in clinical trials in younger patients.

Heparin-induced thrombocytopenia was rarely reported in clinical studies of tinzaparin (incidence approximately 1%). The drug appears well tolerated, with no evidence of placental transfer, in pregnant women. Effects of tinzaparin on liver function tests are transient and do not normally require cessation of therapy.

Various sections of the manuscript reviewed by: D. Bergqvist, Department of Surgery, Akademiska Sjukhus, Uppsala, Sweden; F. Depasse, Laboratoire Claude-Lévy, Clinical Research Department, Ivry-sur-Seine, France; S. Eichinger, Department of Internal Medicine, Division of Hematology and Hemostasis, Medical University of Vienna, Vienna, Austria; J. Fareed, Loyola University Medical Center, Maywood, Illinois, USA; S. Haas, Institut für Experimentelle Onkologie und Therapieforschung, Munich, Germany; S.A. Mousa, Albany College of Pharmacy, Albany, New York, USA; G. Pineo, Thrombosis Research Unit, The University of Calgary, Calgary, Alberta, Canada; A. Planes, Clinique Radio-Chirugicale du Mail, La-Rochelle, France; A. Turpie, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Data Selection

Sources: Medical literature published in any language since 1980 on tinzaparin sodium, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘tinzaparin’ or ‘tinzaparin sodium’ or ‘logiparin’ and ‘thromboembolism’. EMBASE search terms were ‘tinzaparin’ or ‘tinzaparin sodium’ or ‘logiparin’ and ‘thromboembolism’. AdisBase search terms were ‘tinzaparin’ or ‘tinzaparin-sodium’ or ‘logiparin’ and ‘thromboembolism’. Searches were last updated 28 May 2004.
Selection: Studies in patients with thromboembolic disease who received tinzaparin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Tinzaparin sodium, venous thromboembolism, deep vein thrombosis, pulmonary embolism, pharmacodynamics, pharmacokinetics, therapeutic use.