A Comparative Pharmacodynamic Study of Anti-Xa Activity To Evaluate the Accumulation Effect of Tinzaparin and Enoxaparin Given at Prophylactic Dose over 8 Days in Medical Elderly Patients with Impaired Renal Function.

Rationale: LMWHs accumulate in patients with impaired renal function. As this accumulation depends on heparin chain length and subsequent reticulo-endothelial/renal elimination/catabolism LMWHs of different degree of depolymerisation (different distribution and length of heparin chains) should have different pharmacodynamic profile. Do these differences contribute to accumulation of LMWHs in case of renal insufficiency?

Patients, methods and material: An open randomized parallel group trial has been conducted. The primary objective was to detect any accumulation effect of two LMWHs, enoxaparin and tinzaparin, after repeated administration of a prophylactic dose over 8 days in elderly patients (age >75 years) with impaired renal function (creatinine clearance between 20 and 50 ml/min)and body weight <65Kg. Patients were randomized in two parallel groups and received either enoxaparin (Lovenox^®) 4000 IU, or tinzaparin (innohep^®) 4500 UI. The anti-Xa and the anti-IIa activities have been measured on the 1^st and the 8^th days of treatment. Blood samples were taken at 0, 2, 4, 5, 6, 9, 12, 16, 24 hours after the injection of the study drug. The primary end point was the accumulation factor calculated as a ratio between the maximal Anti-Xa activity (Amax) observed on day 8 and the Amax observed on day 1. We also compared the values of the area under the time activity curve 0–24 hours post dosing (AUC_0–24) and the residual activity 24 hours after the injection (A h24) observed on day 8 with the respective values observed on day 1. The laboratory analysis of pharmacodynamic data was blinded with regard to the allocation of treatment.

Results: 55 patients have been included (mean age 87.9 ± 5.5 years). The mean renal creatinine clearance is 34.7± 11.4 ml/min; the mean body weight is 52.3± 8.6 kg. The main pharmacokinetic data are summarized in the table below.

Discussion: In this pharmacodynamic study, a statistically significant accumulation effect was observed after 8 days of prophylactic treatment with enoxaparin but not with tinzaparin. These results reflect the impact of different chain lengths of LMWHs on elimination patterns in elderly patients with impaired renal function.

Trials based on clinical endpoints should be conducted to evaluate the clinical relevance of these observations