Abstract
Since low-molecular-weight heparins (LMWHs) are eliminated preferentially via the kidneys, the potential for accumulation of these agents (and an increased risk of bleeding) is of particular concern in populations with a high prevalence of renal impairment, such as the elderly and patients with cancer. The risk of clinically relevant accumulation of anticoagulant activity as a result of a reduction in renal elimination appears to differ between LMWHs. This review describes the elimination pathways for LMWHs and assesses whether the relative balance between renal and non-renal (cellular) clearance may provide a mechanistic explanation for the differences in accumulation that have been observed between LMWHs in patients with impaired renal function. Clearance studies in animals, cellular binding studies and clinical studies all indicate that the balance between renal and non-renal clearance is dependent on the molecular weight (MW): the higher the MW of the LMWH, the more the balance is shifted towards non-renal clearance. Animal studies have also provided insights into the balance between renal and non-renal clearance by examining the effect of selective blocking of one of the elimination pathways, and it is most likely that cellular clearance is increased to compensate for decreased renal function. Tinzaparin (6,500 Da) has the highest average MW of the marketed LMWHs, and there is both clinical and preclinical evidence for significant non-renal elimination of tinzaparin, making it less likely that tinzaparin accumulates in patients with renal impairment compared with LMWHs with a lower MW distribution. On the basis of our findings, LMWHs that are less dependent on renal clearance may be preferred in patient populations with a high prevalence of renal insufficiency.
Highlights
Low-molecular-weight heparins (LMWHs) are not single, well-described compounds; they are mixtures of glycosaminoglycan chains with different chain lengths, different biological activities and varying sulfation patterns [1]
The results suggest that renal excretion is less important for the overall elimination of tinzaparin compared with enoxaparin, which has an average molecular weight (MW) in the lowest range for LMWHs
Probenecid, a renal organic anion inhibitor, decreased the renal tubular uptake of the heparins, whereas cimetidine, a renal cation inhibitor, had no effect [16]. These findings suggest that renal excretion of unfractionated heparin (UFH) and LMWH primarily reflects tubular uptake via an organic anion transport mechanism
Summary
Low-molecular-weight heparins (LMWHs) are not single, well-described compounds; they are mixtures of glycosaminoglycan chains with different chain lengths, different biological activities and varying sulfation patterns [1]. No dose reduction of tinzaparin is needed in patients with estimated creatinine clearance (CrCl) ≥20 mL/min [5] This is supported by several clinical studies that indicate that there is no clinically significant accumulation of anti-Xa activity (the standard marker of LMWH anticoagulant activity) after repeated once-daily dosing with prophylactic [6] or therapeutic [7,8,9] doses of tinzaparin in patients with renal impairment (CrCl down to 20 mL/min). One of these studies compared prophylactic doses of tinzaparin and enoxaparin in elderly patients with moderate/severe renal impairment (CrCl 20–50 mL/min) [6]. These clinical data are consistent with the hypothesis that MW may influence the extent of renal clearance of LMWHs, with the elimination of LMWHs with low average MW, such as enoxaparin, being more dependent on intact renal function than LMWHs with high average MW, such as tinzaparin
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