No accumulation of the peak anti‐factor Xa activity of tinzaparin in elderly patients with moderate‐to‐severe renal impairment: the IRIS substudy

Abstract

Summary. Background: In the elderly, concerns have been raised regarding the risk of accumulation of low molecular weight heparins, owing to their renal elimination. Although data exist for tinzaparin, they are observational. Objectives: To assess whether: (i) there was an accumulation of anti‐factor Xa activity; and (ii) there was any relationship between anti‐FXa activity and age, weight, creatinine clearance or clinical outcomes in patients with moderate‐to‐severe renal impairment receiving tinzaparin (175 IU kg−1 per 24 h) for acute venous thromboembolism. Methods: In 38 centers participating in the Innohep in Renal Insufficiency Study (IRIS), peak plasma anti‐FXa activity was measured on day 2/day 3 and on day 5 or at visit S (VS) (end of tinzaparin treatment). There was considered to be absence of accumulation if the 90% confidence interval (CI) of the (anti‐FXa day 5/VS)/(anti‐FXa day 2/3) ratio did not exceed the predefined limit of 1.25. Results: Eighty‐seven patients, with a mean age of 83 ± 5 years (range: 75–99 years) and a mean creatinine clearance (CrCl) of 40.8 mL min−1, 24.1% of whom had severe renal impairment, were included. The mean duration of tinzaparin treatment was 8.4 days. No significant accumulation was detected: the mean accumulation ratio was 1.06 (90% CI 1.01–1.11). There was no correlation between the accumulation ratio and age, weight, or CrCl. The mean anti‐FXa activity did not differ significantly between the eight patients who experienced clinically relevant bleeding and those who did not. Conclusions: No accumulation of anti‐FXa activity was observed in elderly patients with renal impairment receiving therapeutic doses of tinzaparin, suggesting that there is no need for systematic anti‐FXa monitoring in these patients. The high proportion of high molecular weight moieties in tinzaparin may account for its reduced dependence on renal elimination.

Pharmacology of Heparin and Related Drugs

“…However, although LMWHs are now standard therapy for VTE treatment and prophylaxis (Dalen, 2002b;Gray et al, 2008;Garcia et al, 2012;Kearon et al, 2012), UH may be more suitable in patients considered to be at a high risk of bleeding (Garcia et al, 2012;Cohen et al, 2014), owing to the relatively rapid cessation of anticoagulant effects upon termination of the infusion and, where necessary, greater susceptibility to reversal by protamine administration (Garcia et al, 2012;Pai and Crowther, 2012). Furthermore, UH with dosing guided by APTT monitoring is the agent of choice in patients with significant impairment of renal function , in whom the rate of LMWH clearance tends to be reduced, thus predisposing these patients to bleeding, although not all LMWH preparations are equally affected in this respect (Rabbat et al, 2005;Lim et al, 2006;Cook et al, 2008;Siguret et al, 2011;Johansen and Balchen, 2013) and it may be appropriate in selected patients to use LMWH with dose adjustment based on anti-Xa measurements (Garcia et al, 2012). In general terms, however, the convenience of fixed-dosage regimens with once-or twice-daily administration-afforded to LMWHs by their more predictable pharmacokinetic profile, as well as the lack of requirement for routine laboratory monitoring (Gray et al, 2008;Weitz and Weitz, 2010) -makes LMWHs the more attractive agents.…”

Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 2: treatment

“…No correlation between the accumulation ratio and age, weight, or creatinine clearance was observed. The trial was stopped prematurely because of a difference in mortality favouring the ufh group (11.5% vs. 6.3%, p = 0.035) 29,30 . Data for dalteparin use in severe renal dysfunction are limited.…”

“…The review concluded that warfarin should not be used in patients with advancing progressive disease 28 . The prothrombotic tendency of patients with advanced cancer suggests a need for indefinite treatment [28][29][30][31] . Currently, randomized clinical data support the use of lmwh treatment for 3-6 months 11,12 is often given for 6 months.…”

Evidence-Based Guidance on Venous Thromboembolism in Patients with Solid Tumours

“…Among patients with moderate renal impairment (creatinine clearance 30-50 mL/min) who received therapeutic enoxaparin (1 mg/kg every 12 hours or 1.5 mg/kg once daily) for 6 months, clinically relevant bleeding occurred in 22% (13 of 59); such bleeding occurred in 6% of patients (6 of 105) with normal renal function (odds ratio: 3.9; 95% ci: 0.97 to 15.6; p = 0.055) 55 . Therapeutic and prophylactic doses of tinzaparin have been shown to be a safer alternative to other lmwh options in patients with renal insufficiency (serum creatinine ≥300 μmol/L and creatinine clearance > 20 mL/min, or creatinine clearance 20-30 mL/ min) [56][57][58] . The American College of Chest Physicians (accp) guidelines reference data showing that tinzaparin clearance is not correlated with creatinine clearance, even at a rate as low as 20 mL/min [58][59][60] .…”

“…Therapeutic and prophylactic doses of tinzaparin have been shown to be a safer alternative to other lmwh options in patients with renal insufficiency (serum creatinine ≥300 μmol/L and creatinine clearance > 20 mL/min, or creatinine clearance 20-30 mL/ min) [56][57][58] . The American College of Chest Physicians (accp) guidelines reference data showing that tinzaparin clearance is not correlated with creatinine clearance, even at a rate as low as 20 mL/min [58][59][60] .…”