Randomised Long-Term Comparison of Tinzaparin and Dalteparin in Haemodialysis

Rolinda J.R. Beijering, Hugo ten Cate, Paul Stevens, Raymond Vanholder, Wim T. Van Dorp, Rudolf W. van Olden, Björn Wickström, Per Sprøgel, Jan W. ten Cate

Disclosures

Clin Drug Invest. 2003;23(2) 

In This Article

Abstract and Introduction

Objective and Design: Tinzaparin and dalteparin are low molecular weight heparins (LMWHs) with different pharmacokinetic and pharmacodynamic profiles that may lead to differences in efficacy and safety. In a long-term, multicentre, prospective, randomised trial we compared the efficacy and safety profiles of tinzaparin and dalteparin (starting doses were adjusted to comparable anti-IIa activity). The sample size was calculated to show a relative difference of 50% in unsatisfactory dialyses with a power of 80% (to prove superiority).
Patients: 159 patients undergoing chronic intermittent haemodialysis were included in the study.
Main Outcome Measures: Efficacy was assessed by scoring the dialyser (from 1 = good, clear dialyser to 4 = total clotting of the dialyser requiring a change of the extracorporeal circuit) and bubble catcher (from 1 = no clots to 4 = severe clotting) after each dialysis. Levels of thrombin antithrombin complexes (TAT) were also determined. Safety was assessed by noting all minor and major bleeding.
Results: The mean anticoagulant dose for tinzaparin during the maintenance phase was about 10% lower than that of dalteparin: 5024 ± 2321 (range 700-12000) anti-Xa IU and 5546 ± 2395 (1875-12913) anti-Xa IU, respectively. No difference was found between treatments in clotting for either the dialyser or the bubble catcher (p = 0.59). TAT levels showed no difference between tinzaparin and dalteparin. The number of minor bleeds did not differ between treatments: 1.5% (40/2629 dialyses) for tinzaparin and 1.4% (41/2863 dialyses) for dalteparin, and one major bleed occurred in each treatment arm.
Conclusions: Dose calculation of tinzaparin and dalteparin according to anti-IIa activity resulted in equivalent efficacy and safety, although this was achieved with a 10% lower dose of tinzaparin measured in anti-Xa IU. Both LMWHs can be safely administered over a wide dosage range in patients undergoing long-term intermittent haemodialysis.

In many countries low molecular weight heparins (LMWHs) have replaced unfractionated heparin for indications including the prophylaxis and treatment of thrombosis.[1,2,3] LMWH preparations have a lower mean molecular weight, increased bioavailability and a longer half-life than unfractionated heparin, and dose-independent clearance.[1,2,3,4] These properties make LMWHs more predictable anticoagulants than unfractionated heparin, which is advantageous during haemo-dialysis.

The main advantage of LMWH over unfractionated heparin in haemodialysis is that one predialysis intravenous bolus injection is sufficient to perform the procedure.[4] For example, a single bolus of 4250 IU of tinzaparin reduced dialyser clotting significantly compared with unfractionated heparin during long-term haemodialysis (p < 0.01).[5] In this study there was no difference in bleeding time after decannulation or in clotting in the venous chamber. Similarly, a dose-finding study demonstrated that a single bolus dose of dalteparin 70 IU/kg effectively inhibited significant coagulation in the bubble trap or dialyser during long-term haemodialysis.[6] Single bolus doses of other LMWHs have demonstrated a decrease in clot formation compared with a continuous infusion of unfractionated heparin.[7]

Different chemical methods are used to manufacture the LMWHs from crude unfractionated heparin (for example, nitrous acid depolymerisation for dalteparin and heparinase digestion for tinzaparin); the different anti-Xa: anti-IIa ratios result in different pharmacokinetic and biological properties[8,9] ( Table I ). It is therefore possible that the structure and pharmacokinetic profiles of the different LMWHs could result in different efficacy and safety profiles. It is clinically important to recognise that each LMWH is a distinct therapeutic entity, and that extrapolation of properties from one LMWH to another without sufficient data is unwise.

The practicalities of dosage adjustment of unfractionated heparin and LMWH when used for anticoagulation during haemodialysis have been investigated. Dosage of each LMWH should be individualised, since a switch from unfractionated heparin to LMWH, or dosage adjustment for patients already taking a LMWH, can result in an altered coagulation tendency with important clinical consequences.[13,14] In the tinzaparin study cited earlier, the conversion ratio of LMWH to unfractionated heparin correlated significantly with blood flow rate and type of dialyser: the minimum necessary dose of tinzaparin correlated with body-weight, blood flow rate and duration of dialysis, and was influenced by the make of dialyser.[5]

It is known that tinzaparin has greater anti-IIa activity than dalteparin, resulting in an anti-Xa: anti-IIa ratio of 1.5-2.5 compared with 2-2.5 for dalteparin.[15] This could have important implications for clinical practice, but to date few studies have directly compared LMWHs. Dalteparin and tinzaparin are LMWHs that have independently been shown to be effective anticoagulants during haemodialysis.[5,16,17,18,19,20] When we conducted this study dalteparin was the LMWH of choice in haemodialysis, with a well documented safety and efficacy profile. We wished to test the relatively new drug tinzaparin against this established LMWH. In this long-term, prospective, randomised, multicentre, assessor-blinded clinical trial we evaluated the absolute and relative efficacy and safety of these two LMWHs after administration to patients undergoing long-term intermittent haemodialysis.

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