Tinzaparin and other low-molecular-weight heparins: what is the evidence for differential dependence on renal clearance?

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.

Treatment with Dalteparin is Associated with a Lower Risk of Bleeding Compared to Treatment with Unfractionated Heparin in Patients with Renal Insufficiency

“…There have been several animal model studies that have highlighted the unique pharmacokinetics of dalteparin that serve as the biological grounding for our favorable results in CKD patients. 18 It has been postulated that the mechanisms of heparin catabolism consist of a balance between a saturable elimination via the reticuloendothelial system and the non-saturable renal tubular excretion. [18][19][20] Various clearance studies in animal models and clinical settings have shown that the higher LMWHs such as tinzaparin (6,500 Da) and dalteparin (5,700 Da) have a faster, dose dependent clearance, suggesting greater involvement of the endothelial clearance pathway with increasing molecular weights and less renal clearance dependency.…”

“…18 It has been postulated that the mechanisms of heparin catabolism consist of a balance between a saturable elimination via the reticuloendothelial system and the non-saturable renal tubular excretion. [18][19][20] Various clearance studies in animal models and clinical settings have shown that the higher LMWHs such as tinzaparin (6,500 Da) and dalteparin (5,700 Da) have a faster, dose dependent clearance, suggesting greater involvement of the endothelial clearance pathway with increasing molecular weights and less renal clearance dependency. 21,22 Rabbat and his group reported all patients who experienced bleeding on dalteparin thromboprophylaxis had trough anti-X a levels below the detection threshold.…”

Thrombo-Embolic Events in Cancer Patients with Impaired Renal Function

“…These data have shown that only tinzaparin has an unchanged apparent half-life when renal function declines as far as to 20 mL/min [18]. Other LMWHs, such as enoxaparin or dalteparindo show a degree of drug accumulation as the apparent half-life increases with lowerrenal filtration, especially when usual therapeutic doses are maintained in this type of patients [18,19].…”

“…There is a well-established correlation between LMWH molecular weight and its excretion. The higher the weight, the more the LMWH is excreted through the reticulo-endothelial system, and not through the kidney route [18]. This has significant implications upon the in vivo pharmacokinetic behavior of the different LMWH compounds, as shown in Figure 5 [19].…”

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

“…Of the available lmwhs, tinzaparin has the highest average molecular weight at 6500 Da, compared with enoxaparin at 4400 Da 54 . 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 .…”