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ARTICLE

Low-Molecular-Weight Heparin Compared with Intravenous Unfractionated Heparin for Treatment of Pulmonary Embolism

A Meta-Analysis of Randomized, Controlled Trials

Daniel J. Quinlan, MBBS; Andrew McQuillan, MBBS; and John W. Eikelboom, MBBS

3 February 2004 | Volume 140 Issue 3 | Pages 175-183

Background: Low-molecular-weight heparin has greatly simplified the management of deep venous thrombosis. However, for patients who present with pulmonary embolism, the role of low-molecular-weight heparin is uncertain and unfractionated heparin remains widely used.

Purpose: To compare the efficacy and safety of fixed-dose subcutaneous low-molecular-weight heparin with that of dose-adjusted intravenous unfractionated heparin to treat acute pulmonary embolism.

Data Sources: The MEDLINE, EMBASE, and Cochrane Library databases were searched up to 1 August 2003. Additional data sources were manual searches of abstract proceedings and personal contact with investigators and pharmaceutical companies.

Study Selection: Randomized trials comparing fixed-dose subcutaneous low-molecular-weight heparin with dose-adjusted intravenous unfractionated heparin for the treatment of nonmassive symptomatic pulmonary embolism or asymptomatic pulmonary embolism in the context of symptomatic deep venous thrombosis.

Data Extraction: Two reviewers independently selected studies and extracted data on study design; quality; and clinical outcomes, including symptomatic venous thromboembolism, death, and major and minor bleeding. Odds ratios for individual outcomes were calculated for each trial and were pooled by using the Mantel–Haenszel method.

Data Synthesis: Fourteen trials involving 2110 patients with pulmonary embolism met the inclusion criteria. Separate outcome data for patients with pulmonary embolism were not available from 2 trials (159 patients), leaving 12 trials for meta-analysis. Compared with unfractionated heparin, low-molecular-weight heparin was associated with a non–statistically significant decrease in recurrent symptomatic venous thromboembolism at the end of treatment (1.4% vs. 2.4%; odds ratio, 0.63 [95% CI, 0.33 to 1.18]) and at 3 months (3.0% vs. 4.4%; odds ratio, 0.68 [CI, 0.42 to 1.09]). Similar estimates were obtained for patients who presented with symptomatic pulmonary embolism (1.7% vs. 2.3%; odds ratio, 0.72 [CI, 0.35 to 1.48]) or asymptomatic pulmonary embolism (1.2% vs. 3.2%; odds ratio, 0.53 [CI, 0.15 to 1.88]). For major bleeding complications, the odds ratio favoring low-molecular-weight heparin (1.3% vs. 2.1%; odds ratio, 0.67 [CI, 0.36 to 1.27]) was also not statistically significant.

Conclusions: Fixed-dose low-molecular-weight heparin treatment appears to be as effective and safe as dose-adjusted intravenous unfractionated heparin for the initial treatment of nonmassive pulmonary embolism.

Editors' Notes Context Several trials have compared benefits and harms of fixed-dose subcutaneous low-molecular-weight heparin with dose-adjusted intravenous unfractionated heparin in patients with pulmonary embolus. Contribution The meta-analysis of 12 randomized trials compared the 2 heparin-based therapies and found nonstatistically significant reductions in risks for recurrent thromboembolism and major bleeding with low-molecular-weight heparin. Implication Low-molecular-weight heparin may be a safe and efficacious alternative to unfractionated heparin for some patients with pulmonary embolus. Cautions Small numbers of events in the trials limited the authors' ability to precisely determine whether the 2 therapies had similar or different effects. –The Editors

 

Author and Article Information

From King's College Hospital, London, United Kingdom; and Royal Perth Hospital and the School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.

Acknowledgments: The authors thank the authors of primary studies included in our meta-analysis (J. Cade, I. Campbell, D. Conen, S. Findik, A. Gallus, C. Kirchmaier, P. Kuijer, S. Laporte, S. Medlicott, P. Prandoni, and C. Thery) and R. Bejuit and S. Combe from Aventis Pharma; S. Wurzinger and F. Misselwitz from Knoll Pharmaceuticals; E. Lindenstrøm and L. Thomassen from Leo Pharmaceuticals; J. Brom and H. Bachmann from Novartis Pharmaceuticals; J. Schoenfelder, C. Fellenius, and A. Holmqvist, for Pharmacia Corporation; and J.-E. Joire from Sanofi-Synthelabo for assistance in verifying the accuracy of the data and providing missing data.

Potential Financial Conflicts of Interest:Honoraria: D.J. Quinlan (Aventis, Sanofi-Synthelabo), J.W. Eikelboom (Aventis, Pharmacia, Sanofi-Synthelabo); Grants received: J.W. Eikelboom (Aventis, Sanofi-Synthelabo).

Requests for Single Reprints: John W. Eikelboom, MBBS, Department of Haematology, Royal Perth Hospital, Wellington Street, Perth WA 6001, Australia; e-mail, john.eikelboom{at}health.wa.gov.au.

Current Author Addresses: Dr. Quinlan: Department of Radiology, King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom.

Drs. McQuillan and Eikelboom: Department of Haematology, Royal Perth Hospital, Wellington Street, Perth WA 6001, Australia.

Author Contributions: Conception and design: D.J. Quinlan, A. McQuillan, J. Eikelboom.

Analysis and interpretation of the data: D.J. Quinlan, A. McQuillan, J. Eikelboom.

Drafting of the article: D.J. Quinlan, A. McQuillan, J. Eikelboom.

Critical revision of the article for important intellectual content: D.J. Quinlan, A. McQuillan, J. Eikelboom.

Final approval of the article: D.J. Quinlan, A. McQuillan, J. Eikelboom.

Statistical expertise: J. Eikelboom.

Administrative, technical, or logistic support: J. Eikelboom.

Collection and assembly of data: D.J. Quinlan, A. McQuillan, J. Eikelboom.

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