Low Molecular Weight Heparin and Bleeding in Patients with Severe Renal Failure: A Meta-Analysis.

Background: Dose adjustment or monitoring of low molecular weight heparin (LMWH) is commonly recommended in patients with severe renal insufficiency (creatinine clearance [CrCl] ≤ 30 ml/min) but little evidence supports this recommendation.

Purpose: To compare the risk of major bleeding in LMWH-treated patients with CrCl ≤ 30 ml/min versus > 30 ml/min using standard weight-adjusted therapeutic LMWH doses, empirically adjusted LMWH doses and prophylactic LMWH doses.

Data sources: Electronic databases (MEDLINE, EMBASE, Cochrane Library), reference lists and contact with experts.

Study selection: Observational or subgroups of randomized studies that included non-dialyzed patients with varying degrees of renal function who were treated with LMWH and which reported CrCl and major bleeding.

Data extraction: Two reviewers independently selected studies and extracted data on patient characteristics, renal function, LMWH treatment and major bleeding. The pooled relative risk (RR) of major bleeding in patients with CrCl ≤ 30 versus > 30 ml/min was calculated by the Mantel-Haenszel method.

Data synthesis: In 12 studies involving 4971 patients (10 studies of 4741 patients using enoxaparin; 2 studies of 230 patients using tinzaparin), LMWH significantly increased the risk of major bleeding in patients with CrCl ≤ 30 compared with > 30 ml/min (5.0% vs. 2.4%, RR 2.34, 95% confidence interval [CI]: 1.46 to 3.74; P = 0.0004; number needed to harm [NNH] = 38). When analyzed according to LMWH preparation, increased major bleeding was evident in studies of standard weight-adjusted therapeutic dose enoxaparin (8.3% vs. 2.4%, RR 2.96; 95% CI: 1.63 to 5.37, NNH = 17) but not in studies using empirically adjusted enoxaparin doses (0.9% vs. 1.9%, RR 1.06; 95% CI: 0.23 to 4.97), P for heterogeneity = 0.82. There were insufficient studies using tinzaparin and prophylactic doses of enoxaparin.

Limitations: Only 2 LMWH preparations were evaluated and only 2 studies used tinzaparin. Data are observational and the potential for confounding cannot be excluded.

Conclusions: Non-dialysis dependent patients with CrCl ≤ 30 ml/min who are treated with therapeutic doses of enoxaparin have an increased risk of major bleeding. Empiric dose reduction of enoxaparin may reduce the risk of bleeding and merits further evaluation. No conclusions can be drawn regarding other LMWHs.