Dose Finding Study of a Low Molecular Weight Heparin, Innohep, in Haemodialysis

Abstract

SummaryA pilot investigation was performed with Innohep, a low molecular weight (LMWH) preparation (peak maximum molecular mass 3,000-6,000), to determine possible dose regimens for patients undergoing regular maintenance haemodialysis for chronic renal failure. Results from this study suggested that suppression of macroscopic clot formation and fibrinopeptide A (FPA), a marker of fibrin formation, could be achieved following bolus injections rather than bolus injections and an infusion. On the basis of these preliminary findings, a randomised crossover study was performed in eight patients undergoing regular maintenance haemodialysis for 5-7 h to determine the effective antithrombotic dose of this LMWH. Single i.v. bolus doses of 1,250 AFXa u, 2,500 AFXa u and 5,000 AFXa u (n = 7-8) were compared to an UFH regime of 5,000 iu + 1,500 iu/h. Excessive clot formation in the dialyser bubble trap, necessitating additional UFH to enable completion of a prolonged (up to 7 h) dialysis, was observed in all patients on the 1,250 AFXa u dose (mean duration of dialysis prior to UFH, 3 h) but in a single patient only receiving the other LMWH doses. A dose-related response in the AFXa activity, measured by chromogenic substrate (CS) assay was seen in the three LMWH groups, with levels declining significantly (p <0.05) from 1-7 h. This contrasted with the constant levels maintained during dialysis with UFH. FPA levels were significantly elevated after 2 h following the 1,250 AFXa u bolus and after 4 h following the 2,500 AFXa u bolus. There was no significant difference in FPA levels between the 5,000 AFXa u bolus and UFH. β-thromboglobulin (pTG) levels rose significantly towards the end of dialysis in all LMWH groups and, at 5 h, were significantly increased following the 5,000 AFXa u and 2,500 AFXa u doses when compared to the UFH regime. AFXa levels correlated negatively with FPA levels (r = -0.62; p <0.01). In conclusion, for administration of Innohep, a bolus dose of 2,500 AFXa u would appear to be sufficient for dialyses of short duration (up to 4 h), whilst a 5,000 AFXa u bolus is as effective as UFH for a 6 h dialysis. AFXa activity measured by CS assay is related to inhibition of fibrin formation and can be used for monitoring purposes.

Safety and Efficacy of Low Molecular Weight Heparins for Hemodialysis in Patients with End-Stage Renal Failure

“…Consequently, the optimal UFH dose was compared with potentially suboptimal doses of LMWH; use of subtherapeutic LMWH doses might both decrease bleeding and increase circuit thrombosis. This is illustrated by one dose-finding study in which a single dose of tinzaparin 1250 IU resulted in all dialyses complicated by thrombosis but only one dialysis that required additional UFH when tinzaparin doses of 2500 and 5000 IU were used (32). Another study found that circuit clotting occurred more frequently with LMWH compared with UFH in the early phase of the study; 26 of 32 patients required dose adjustments, with 20 of these patients requiring increased LMWH doses (40).…”

“…A run-in phase was used in two studies, in which an individualized (optimal) LMWH dose was determined before (43) or after randomization (31). Two studies were dose-finding studies (30,32). In three studies, the patient's hematocrit or duration of hemodialysis determined the initial LMWH dose (31,34,43).…”

“…Thrombosis that occurred within the dialysis circuit was analyzed in five of 11 possible studies (28,29,32,36,40) (Table 7). Two studies reported units that could not be converted to a proportion of hemodialysis sessions (11,30), and another two reported clotting per number of patients affected (31,33).…”

The Low Molecular Weight Heparin, Tinzaparin, in Thrombosis and Beyond

“…Plasma levels of TFPI increased rapidly following subcutaneous injection of tinzaparin sodium reaching maximum and sustained levels for up to 5 h. The absolute bioavailability was approximately 90% based on anti-factor Xa activity (55) and 95% based on TFPI release (45).…”

“…It is superior to warfarin in the prophylaxis of thromboembolism in subjects undergoing orthopedic joint (hip or knee) replacement surgery (28,29,36,57). It is also an effective anticoagulant for extracorporeal circuits in hemodialysis (55). Tinzaparin has been marketed for over 10 years in Europe, over 6 years in Canada, and was recently approved by the Food and Drug Administration (FDA) in the USA.…”