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

2 May 2006 | Volume 144 Issue 9 | Pages 673-684

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.

Editors' Notes Context The risks of low-molecular-weight heparin (LMWH) in patients with severe renal insufficiency are not clear. Contribution In this review of 12 studies, patients with severe renal insufficiency receiving LMWH had an increased risk for major bleeding events. Four studies found that fixed-dose enoxaparin had greater anticoagulant effects in these patients. Three studies suggested that empirically dose-adjusted enoxaparin might not increase anticoagulant effects. Cautions Evidence relating to LMWHs other than enoxaparin was scant. Implications Patients with severe renal insufficiency receiving standard fixed-dose enoxaparin have greater anticoagulant effects and a higher risk for major bleeding. Empirical dose adjustment may reduce the risk for such events. —The Editors

 

Author and Article Information

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{at}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.

Read all Rapid Responses

Low-Molecular-Weight Heparin And Bleeding in Patients with Severe Renal Insufficiency

T. S. Dharmarajan, et al.

Annals Online, 6 Jun 2006 [Full text]