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Meta-Analysis: Low-Molecular-Weight Heparin and Bleeding in Patients with Severe Renal Insufficiency

Wendy Lim, MD, BSc; Francesco Dentali, MD; John W. Eikelboom, MBBS; and Mark A. Crowther, MD, MSc
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From McMaster University and Hamilton General Hospital, Hamilton, Ontario, Canada, and University of Insubria, Varese, Italy.

Acknowledgments: The authors thank Dr. Qilong Li for providing additional statistical analyses and the authors of the primary studies, Drs. L. Lalonde, I. Mahe, V. Siguret, and N. Thorevska, who kindly provided information included in the meta-analysis.

Grant Support: Dr. Crowther is a Career Investigator of the Heart and Stroke Foundation of Canada; Dr. Eikelboom holds a Tier II Canada Research Chair in Cardiovascular Medicine from the Canadian Institutes for Health Research; and Dr. Lim is the recipient of a Graduate Scholarship from the Canadian Institutes of Health Research.

Potential Financial Conflicts of Interest: Consultancies: M.A. Crowther (AstraZeneca, Pfizer/Pharmacia, Sanofi-Aventis, GlaxoSmithKline, La Jolla Pharmaceutical Corporation, Leo Laboratories, Sandoz); Honoraria: J.W. Eikelboom (Pharmacia Corp., Sanofi, Aventis), M.A. Crowther (Pfizer/Pharmacia, Sanofi-Aventis, GlaxoSmithKline, Leo Laboratories, Calea, Novo Nordisk); Grants received: W. Lim (Sanofi-Aventis), J.W. Eikelboom (Sanofi, Aventis), M.A. Crowther (Pfizer/Pharmacia, Sanofi-Aventis, Leo Laboratories).

Corresponding Author: Wendy Lim, MD, BSc, St. Joseph's Hospital, 50 Charlton Avenue East, Room L208, Hamilton, Ontario L8N 4A6, Canada; e-mail, limwp@mcmaster.ca.

Current Author Addresses: Drs. Lim and Crowther: St. Joseph's Hospital, 50 Charlton Avenue East, Room L208, Hamilton, Ontario L8N 4A6, Canada.

Dr. Dentali: Department of Medicine, University of Insubria, Viale Borri 57, 21100 Varese, Italy.

Dr. Eikelboom: Hamilton Health Sciences, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Ann Intern Med. 2006;144(9):673-684. doi:10.7326/0003-4819-144-9-200605020-00011
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Background: Dose adjustment or laboratory monitoring of low-molecular-weight heparin (LMWH) is commonly recommended for patients with severe renal insufficiency (creatinine clearance ≤30 mL/min), but the basis for this recommendation is unclear.

Purpose: To compare levels of anti-Xa heparin and risk for major bleeding in LMWH-treated patients with a creatinine clearance of 30 mL/min or less versus those with a creatinine clearance greater than 30 mL/min by using standard weight–adjusted therapeutic doses, empirically adjusted doses, or prophylactic doses of LMWH.

Data Sources: Electronic databases (MEDLINE, EMBASE, and the Cochrane Library) searched to December 2005 with no language restrictions. The authors also searched reference lists and contacted experts.

Study Selection: Observational or subgroups of randomized studies that included non–dialysis-dependent patients with varying degrees of renal function who were treated with LMWH and reported creatinine clearance and anti-Xa levels or major bleeding.

Data Extraction: Two reviewers independently selected studies and extracted data on patient characteristics, renal function, LMWH treatment, anti-Xa levels, and major bleeding. The pooled odds ratio of major bleeding in patients with a creatinine clearance of 30 mL/min or less was calculated by using the Peto method.

Data Synthesis: Eighteen studies using 3 preparations of LMWH (15 studies using enoxaparin, 2 using tinzaparin, and 1 using dalteparin) were included. Peak anti-Xa levels measured 4 hours after a subcutaneous injection were statistically significantly higher in patients with a creatinine clearance of 30 mL/min or less compared with those with a creatinine clearance greater than 30 mL/min in studies that used a standard therapeutic dose of enoxaparin (4 studies) but not in studies of empirically dose-adjusted enoxaparin (3 studies). Data were insufficient to assess the relationship between anti-Xa and renal function for prophylactic doses of enoxaparin and therapeutic doses of tinzaparin or dalteparin. In 12 studies involving 4971 patients, LMWH was associated with a statistically significant increase in the risk for major bleeding in patients with a creatinine clearance of 30 mL/min or less compared with those with a creatinine clearance greater than 30 mL/min (5.0% vs. 2.4%; odds ratio, 2.25 [95% CI, 1.19 to 4.27]; P = 0.013). When analyzed according to LMWH preparation, major bleeding was increased when a standard therapeutic dose of enoxaparin was used (8.3% vs. 2.4%; odds ratio, 3.88 [CI, 1.78 to 8.45]) but may not be increased when an empirically adjusted dose of enoxaparin is used (0.9% vs. 1.9%; odds ratio, 0.58 [CI, 0.09 to 3.78]; P = 0.23 for heterogeneity). There were insufficient studies to assess the risk for major bleeding with tinzaparin, dalteparin, and prophylactic doses of enoxaparin.

Limitations: The data for tinzaparin and dalteparin were limited. Data are observational, and the potential for confounding cannot be excluded.

Conclusions: Non–dialysis-dependent patients with a creatinine clearance of 30 mL/min or less who are treated with standard therapeutic doses of enoxaparin have elevated levels of anti-Xa and an increased risk for major bleeding. Empirical dose adjustment of enoxaparin may reduce the risk for bleeding and merits additional evaluation. No conclusions can be made regarding other LMWHs.


Grahic Jump Location
Figure 1.
Study selection progression.

LMWH = low-molecular-weight heparin.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Peto odds ratio (OR) of major bleeding events in patients with severe renal insufficiency (creatinine clearance ≤30 mL/min) compared with patients without renal insufficiency (creatinine clearance >30 mL/min).
Grahic Jump Location
Grahic Jump Location
Figure 3.
Peto odds ratio (OR) of major bleeding events with enoxaparin in patients with severe renal insufficiency (creatinine clearance ≤30 mL/min) compared with patients without renal insufficiency (creatinine clearance >30 mL/min).
Grahic Jump Location




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Low-Molecular-Weight Heparin And Bleeding in Patients with Severe Renal Insufficiency
Posted on June 6, 2006
T. S. Dharmarajan
Our Lady of Mercy Medical Center
Conflict of Interest: None Declared

To the Editor,

We read with interest the significant information provided in the meta-analysis published recently in the Annals (1) suggesting that patients with severe renal insufficiency on standard doses of enoxaparin have an increased risk for major bleeding, perhaps attributable to elevated levels of Anti-Xa (1). The presence of renal impairment causes a delay in the elimination of enoxaparin; in fact, a linear relationship between anti-factor Xa plasma clearance and steady-state creatinine clearance correlates with decline in enoxaparin clearance and resultant increased anticoagulant activity (2). While the authors and others recommend a reduction in enoxaparin dosage with a creatinine clearance lower than 30 ml/min, pharmacokinetic analysis of anti-Xa activity suggests alterations even in the presence of mild to moderate renal impairment, i.e. even with creatinine clearance lower than 50 mL/min (3).

Further, it is recognized that age related sarcopenia and a decline in creatinie clearance (age or disease related) contribute to errors in interpretation of serum creatinine alone; while creatinine clearance can be determined by using the Cockroft-Gault formula or the MDRD (Modification of Diet in Renal Disease calculator), neither formula has been considered perfect, and the preferred method is controversial (4). Predictions from the formulae also show weak but positive correlations with percentage body fat. Enoxaparin clearance also depends on body weight. Thus enoxaparin dosing ultimately should take into consideration alterations in renal function (including from age), body weight (plus fat distribution), gender and anti-Xa activity in steady state (5). Attention to concomitant medication use is worthwhile.

We are presently in an era where the use of low-molecular weight heparin in healthcare is on the increase, in view of greater awareness to institute measures for thrombo-embolic prophylaxis and treatment. So how do we lower risk of bleeding, but maintain benefit? Perhaps we can educate providers on considerations pertinent to low molecular heparin. The following list provides a start: (1) Enhance awareness of pharmacokinetics; (2) Age and gender considerations; (3) Ideal body weight and fat distribution; (4) Anti-Xa activity: measurement; (5) Calculate GFR, do not dose solely based on serum creatinine; (6) Adjust dose to graded renal function (rather than creatinine clearance < 30 or >30 ml/min) and body weight; and (7) Consider drug-drug interactions e.g. anti -platelet agents.

T.S. Dharmarajan MD, FACP, AGSF Chairman, Department of Medicine Our Lady of Mercy Medical Center Bronx, New York Professor of Medicine, New York Medical College, Valhalla, NY

Amit Sohagia MD Senior Resident in Medicine Our Lady of Mercy Medical Center Bronx, New York 10466 asohagia1204@yahoo.com


1.Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low- molecular-weight heparin and bleeding in patients with severe renal insufficiency. Annals of Internal Medicine 2006; 144(9): 673-84.

2.Chow SL, Zammit K, West K et al. Correlation of antifactor Xa concentrations with renal function in patients on enoxaparin. Journal of Clinical Pharmacology.2003; 43(6): 586-90.

3.Hulot JS, Montalescot G, Lechat P et al. Dosing strategy in patients with renal failure receiving enoxaparin for the treatment of non-St-segment elevation acute coronary syndrome. Clin Pharmacol. 2005; 77(6): 542-52

4.Poggio ED, Hall PM. Estimation of glomerular filtraion rate by creatinine-based formulas: Any room for improvement (editorial). NephSAP. 2006; 5(3): 131-140.

5.Hulot JS, Nantelon C, Urien S, et al. Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment. Therapeutic Drug Monitoring. 2004 Jun; 26(3): 305-10.

Conflict of Interest:

None declared

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