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Low-Molecular-Weight Heparins Compared with Unfractionated Heparin for Treatment of Acute Deep Venous Thrombosis: A Meta-Analysis of Randomized, Controlled Trials

Michael K. Gould, MD, MSc; Anne D. Dembitzer, MD; Ramona L. Doyle, MD; Trevor J. Hastie, PhD; and Alan M. Garber, MD, PhD
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From Veterans Affairs Palo Alto Health Care System, Palo Alto, California; and Stanford University, Stanford, California.

Ann Intern Med. 1999;130(10):800-809. doi:10.7326/0003-4819-130-10-199905180-00003
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Background: Low-molecular-weight heparins may simplify the management of deep venous thrombosis. A critical clinical issue is whether this more convenient therapy is as safe and effective as treatment with unfractionated heparin.

Purpose: To compare the safety and efficacy of low-molecular-weight heparins with those of unfractionated heparin for treatment of acute deep venous thrombosis.

Data Sources: Reviewers identified studies by searching MEDLINE, reviewing references from retrieved articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies.

Study Selection: Randomized, controlled trials that compared a low-molecular-weight heparin preparation with unfractionated heparin for treatment of acute deep venous thrombosis.

Data Extraction: Two reviewers extracted data independently. Reviewers evaluated study quality using a validated four-item instrument.

Data Synthesis: Eleven of 37 studies met inclusion criteria for three major outcomes. Most studies used proper randomization procedures, but only one was double-blinded. Compared with unfractionated heparin, low-molecular-weight heparins reduced mortality rates over 3 to 6 months of patient follow-up (odds ratio, 0.71 [95% CI, 0.53 to 0.94]; P = 0.02). For major bleeding complications, the odds ratio favored low-molecular-weight heparins (0.57 [CI, 0.33 to 0.99]; P = 0.047), but the absolute risk reduction was small and not statistically significant (0.61% [CI, −0.04% to 1.26%]; P = 0.07). For preventing thromboembolic recurrences, low-molecular-weight heparins seemed as effective as unfractionated heparin (odds ratio, 0.85 [CI, 0.63 to 1.14]; P > 0.2).

Conclusions: Low-molecular-weight heparin treatment reduces mortality rates after acute deep venous thrombosis. These drugs seem to be as safe as unfractionated heparin with respect to major bleeding complications and appear to be as effective in preventing thromboembolic recurrences.


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Figure 1.
Primary study and summary odds ratios (ORs) for major bleeding and recurrent thromboembolism.LMWHUFHREM

Odds ratios are indicated by boxes. Horizontal lines represent 95% CIs. Odds ratios less than 1.0 favor low-molecular-weight heparins ( ); odds ratios greater than 1.0 favor unfractionated heparin ( ). The summary odds ratio for major bleeding favors low-molecular-weight heparins, but this finding is not statistically significant under the assumptions of the random-effects model ( ). The CI for the summary odds ratio for recurrent thromboembolism also crosses 1, indicating no statistically significant difference between the treatments. FEM = fixed-effects model.

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Figure 2.
Conventional and cumulative meta-analysis for mortality rates.LMWHOR

The left portion illustrates conventional meta-analysis results showing a statistically significant benefit for low-molecular-weight heparin ( ) treatment. The right portion illustrates the results of cumulative meta-analysis, in which the summary odds ratio ( ) is recalculated after individual studies are added one at a time by year of publication. A statistically significant benefit for low-molecular-weight heparin is apparent after the addition of the third study. The direction and statistical significance of the treatment effect remain constant with the addition of each new study, although the magnitude of the effect lessens slightly over time. FEM = fixed-effects model; REM = random-effects model; UFH = unfractionated heparin.

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Figure 3.
Inverted funnel plot of primary study odds ratios for mortality versus study sample size.solid line with arrow

Publication bias occurs when the decision to submit or publish a study is influenced by the results of the study. A negative trial (one that shows no difference between treatments) might be less likely to be published than a trial with positive results, especially when the trial involves small numbers of participants. In this funnel plot, more small studies fall to the left of the summary treatment effect ( ) than to the right. Several small negative trials may not have been published or identified, under the assumption that primary study results should be evenly distributed around the summary treatment effect. Inverted funnel plots for major bleeding and recurrent thromboembolism were similar in appearance. In contrast, a symmetrical plot centered on the summary treatment effect argues against publication bias. LMWH = low- molecular-weight heparin; UFH = unfractionated heparin.

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