Background: Primarily eliminated by the kidneys, low-molecular-weight heparins (LMWHs) need to be monitored carefully when used in patients with severe renal insufficiency, because of the concern about bioaccumulation, which can increase the risk of bleeding. Individual LMWHs have not been compared with each other in large clinical trials, and currently there is no standard of practice for the use of LMWH in this patient population.

Methods: Computerized queries of PubMed, MEDLINE, and the American Society of Hematology abstract database were performed to identify clinical trials assessing the safety of LMWHs in patients with severe renal failure (creatinine clearance [CrCl] <30 mL/min).

Results: A meta-analysis of 15 studies of enoxaparin and 2 studies of tinzaparin (N = 5201) showed that when compared with patients with a CrCl >30 mL/min, those with a CrCl ≤30 mL/min had more than double the risk of major bleeding and higher peak anti-Xa levels (Lim et al, 2006). Much of this effect was confined to patients who received standard therapeutic doses of enoxaparin (Mahe et al, 2007). A study of medical patients with a reduced CrCl treated with tinzaparin or enoxaparin showed significantly increased mean anti-Xa activity in the enoxaparin group but not in the tinzaparin group, indicating a significant accumulation of enoxaparin but not of tinzaparin (Mahe et al, 2007). Recent data suggest that dalteparin, when used at prophylactic doses, does not bioaccumulate and can be used safely in patients with severe renal impairment (Tincani et al, 2006; Douketis et al, 2007).

Conclusions: Whereas studies suggest that enoxaparin bioaccumulates in patients with severe renal insufficiency (Mahe et al, 2007), dalteparin and tinzaparin do not appear to bioaccumulate to the same degree (Tincani et al, 2006; Mahe et al, 2007; Douketis et al, 2007). These differences may be explained by the fact that smaller LMWH chains (enoxaparin) are cleared primarily by the kidneys, whereas larger chains (dalteparin, tinzaparin) have greater clearance by nonrenal mechanisms. Thus, dalteparin and tinzaparin may be preferred in patients with renal impairment.

Table. Summary of recent trials evaluating dalteparin and tinzaparin in patients with renal impairment

TrialStudy Design/RegimenResults
CrCl = creatinine clearance; DIRECT = Dalteparin’s Influence on Renally Compromised: Anti-Ten-A Study; DVT = deep vein thrombosis; SC = subcutaneous. 
Tincani et al, 2006 N = 115 Patients with acute medical illness and elevated serum CrCl
 Dalteparin 2500 IU (low-risk patients) or 5000 IU (high-risk patients) SC once daily for ≥6 days No evidence of dalteparin bioaccumulation (increased anti-Xa levels) on Day 6, irrespective of renal function
 No correlation between degree of renal impairment and peak anti-Xa level on Day 6 No major bleeding or DVT events 
DIRECT (Douketis et al, 2007) N = 138 Critically ill patients with CrCl <30 mL/min
 Dalteparin, 5000 IU SC once daily for ≤30 days No evidence of dalteparin bioaccumulation Median trough anti-Xa level <0.1 IU/mL
 Major bleeds occurred in 10 patients (7.2%), all with trough anti-Xa <0.12 IU/mL DVT occurred in 7 patients (5.1%) 
Mahe et al, 2007 N = 55 Elderly medical patients with a baseline CrCl between 20 and 50 mL/min
 Enoxaparin 4000 IU SC or tinzaparin 4500 IU SC once daily for 8 days The accumulation factor was not significant for tinzaparin (1.05, P= 0.29), whereas it was significant for enoxaparin (1.22, P<0.0001) by Day 8
 No patient in the study had a thromboembolic event 4 patients given enoxaparin had bleeding events (1 major) vs 5 in the tinzaparin group (2 major) 
TrialStudy Design/RegimenResults
CrCl = creatinine clearance; DIRECT = Dalteparin’s Influence on Renally Compromised: Anti-Ten-A Study; DVT = deep vein thrombosis; SC = subcutaneous. 
Tincani et al, 2006 N = 115 Patients with acute medical illness and elevated serum CrCl
 Dalteparin 2500 IU (low-risk patients) or 5000 IU (high-risk patients) SC once daily for ≥6 days No evidence of dalteparin bioaccumulation (increased anti-Xa levels) on Day 6, irrespective of renal function
 No correlation between degree of renal impairment and peak anti-Xa level on Day 6 No major bleeding or DVT events 
DIRECT (Douketis et al, 2007) N = 138 Critically ill patients with CrCl <30 mL/min
 Dalteparin, 5000 IU SC once daily for ≤30 days No evidence of dalteparin bioaccumulation Median trough anti-Xa level <0.1 IU/mL
 Major bleeds occurred in 10 patients (7.2%), all with trough anti-Xa <0.12 IU/mL DVT occurred in 7 patients (5.1%) 
Mahe et al, 2007 N = 55 Elderly medical patients with a baseline CrCl between 20 and 50 mL/min
 Enoxaparin 4000 IU SC or tinzaparin 4500 IU SC once daily for 8 days The accumulation factor was not significant for tinzaparin (1.05, P= 0.29), whereas it was significant for enoxaparin (1.22, P<0.0001) by Day 8
 No patient in the study had a thromboembolic event 4 patients given enoxaparin had bleeding events (1 major) vs 5 in the tinzaparin group (2 major) 
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Topics:
kidney failure, low-molecular-weight heparin, tinzaparin, enoxaparin, dalteparin, anti factor xa, deep vein thrombosis, renal impairment, hemorrhage, creatinine clearance

Disclosures: Nutescu:Eisai: Speakers Bureau; Sanofi-Aventis: Speakers Bureau; GSK: Speakers Bureau; Bayer: Consultancy; Astra Zeneca: Consultancy. Off Label Use: Use of low-molecular-weight heparins for prophylaxis or treatment in patients with renal insufficiency. Spyropoulos:Sanofi-Aventis: Consultancy; Boehringer Ingelheim: Consultancy; Eisai Inc.: Speakers Bureau.

Lim W, Dentali F, Eikelboom JW, et al. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency.
Ann Intern Med
.
2006
;
144
:
673
–684.
Mahe I, Aghassarian M, Drouet L. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study.
Thromb Haemost
.
2007
;
97
:
581
–586.
Tincani E, Mannucci C, Casolari B, et al. Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study.
Haematologica
.
2006
;
91
:
976
–979.
Douketis J, Cook D, Zytaruk N, Heels-Ansdell D, Anderson D, Geerts W, Meade M, Guyatt G, Crowther M. Dalteparin thromboprophylaxis in critically ill patients with severe renal insufficiency: the DIRECT study.
J Thromb Haemost
2007
; 5 Supplement 2:
P-S-680

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Corresponding author

2008, The American Society of Hematology
2008
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