Low-Molecular-Weight Heparins Compared with Unfractionated Heparin for Treatment of Acute Deep Venous Thrombosis

Low-molecular-weight heparins simplify the treatment of acute deep venous thrombosis because they may be administered subcutaneously once or twice daily, without the need for laboratory monitoring or dose adjustment in most cases (1). A critical clinical issue is whether this more convenient therapy is as safe and effective as treatment with conventional unfractionated heparin. Many randomized, controlled trials have addressed this question (2-12), but several of these studies examined improvement in venography scores rather than clinical outcomes (2, 5-7, 10). Researchers have used meta-analysis to reexamine the results of these studies and have reached mixed conclusions. Some have found low-molecular-weight heparins to be superior to unfractionated heparin with respect to major bleeding complications, thromboembolic recurrences, and mortality rates (13, 14), whereas others have reported nonsignificant trends favoring low-molecular-weight heparins for some or all of these outcomes (15, 16). Several large randomized trials have been conducted since the publication of these previous reviews, including the largest trial of low-molecular-weight heparin treatment (12). We performed this meta-analysis to incorporate the most recent data from clinical trials, to resolve discrepancies among previous reviews, and to obtain precise estimates of clinically important treatment outcomes. In addition, to generate hypotheses for subsequent investigation, we sought to identify sources of variation in primary study results and to relate these sources to differences in trial design and execution. Methods We used systematic methods to identify all relevant published and unpublished studies (17), assess studies for eligibility (18), describe variations in study design and execution, evaluate study quality (19), and quantify the relative benefits of low-molecular-weight heparin treatment (20). Study Identification We attempted to identify all published and unpublished randomized trials that compared a low-molecular-weight heparin preparation with unfractionated heparin for the treatment of acute deep venous thrombosis. An investigator and a professional librarian jointly developed strategies for locating studies published between January 1985 and September 1997 in the MEDLINE database (Appendix). We augmented our MEDLINE search by manually reviewing the reference lists of identified studies and review articles, scanning abstracts from conference proceedings, and contacting investigators and pharmaceutical companies. Study Eligibility Two investigators independently evaluated studies for possible inclusion and subsequently resolved any disagreements by discussion. Investigators were not blinded to journal, author, or institution. Studies were included if they 1) enrolled participants with acute lower-extremity deep venous thrombosis, with or without coexisting pulmonary embolism; 2) randomly assigned participants to treatment groups; 3) compared subcutaneously administered, fixed-dose low-molecular-weight heparin with adjusted-dose unfractionated heparin for the initial treatment of deep venous thrombosis; 4) used objective methods to confirm the initial episode of deep venous thrombosis; and 5) used objective methods to assess one or more clinical outcomes, including major bleeding complications, recurrent thromboembolic events, and mortality rates. For studies to be included in analyses of recurrent thromboembolism and mortality rates, we required that participants be followed for at least 3 months. We excluded dose-ranging studies and studies that permitted a change in the dose of low-molecular-weight heparin during the trial. Abstracts were included only when investigators supplied full reports of their methods and results. Variation in Study Design and Execution One investigator collected data on the following study-level factors: 1) the type of low-molecular-weight heparin preparation studied, 2) the timing of warfarin administration, 3) whether unfractionated heparin was administered to some participants before randomization, 4) whether outpatient treatment with low-molecular-weight heparin was permitted, 5) whether participants with concurrent pulmonary embolism were enrolled, and 6) whether the study used objective and reproducible methods to identify and confirm clinical outcomes. Assessment of Study Quality We adopted the study-quality criteria outlined by Schultz and colleagues [19]. Their criteria included four dimensions: 1) proper generation of the treatment allocation sequence [use of a random-numbers table or a computer program], 2) proper concealment of the allocation sequence [use of sealed envelopes or randomization over the telephone from a central site], 3) double-blinding, and 4) patients lost to follow-up. One investigator extracted data on these dimensions from the primary studies. When details on randomization procedures were not fully specified, we requested additional information from the authors. Improper concealment of the allocation sequence and absence of double-blinding have been shown to be predictors of potential bias in study outcomes (19). Double-blinding is important even when outcomes are confirmed with objective tests because the decision to perform or not to perform diagnostic tests might be subject to bias. Data Extraction Two investigators independently extracted data on three major outcomes: 1) major bleeding complications during the initial heparin treatment period, 2) recurrent thromboembolic events over 3 to 6 months, and 3) mortality rates over 3 to 6 months. They also extracted data on minor bleeding complications, thrombocytopenia, rates of death from major bleeding, rates of death from recurrent thromboembolism, and rates of death in participants with cancer. We accepted the primary study authors' definitions for recurrent deep venous thrombosis, pulmonary embolism, major and minor bleeding, and thrombocytopenia. Data Synthesis and Statistical Analysis We evaluated agreement between raters for the assessment of study inclusion by calculating the observed percentage agreement and the coefficient for inter-rater reliability (21). For each outcome, we calculated the odds ratio, absolute risk reduction, and number needed to treat to prevent one event (NNT) for the individual studies. We then used fixed-effects (22) and random-effects models (23, 24) to estimate summary treatment effects for all studies combined. We performed these calculations by using Meta-Analyst, version 0.983 (Lau J. New England Medical Center, Boston, 1997). To assess the validity of combining results from individual studies, we used the Mantel-Haenszel test for statistical heterogeneity (25). We considered a P value less than 0.05 to be significant for all statistical tests. Sensitivity Analysis and Analysis of Study-Level Factors We performed sensitivity testing for each of the three major outcomes. To assess the robustness of findings over time, we ordered studies chronologically and performed a cumulative meta-analysis (26). To check for possible publication bias, we created inverted funnel plots of individual study results plotted against sample size (27). Funnel plots help to establish whether additional small studies may have been conducted but not published because of negative results. We also calculated the number of missing negative trials that would be needed to change the conclusions of a meta-analysis that showed a statistically significant difference between treatments (28). To identify any studies that exerted a disproportionate influence on the summary treatment effect, we deleted individual studies one at a time. To investigate the possible consequences of excluding abstracts for which we could not obtain full reports, we included available data from these trials in secondary analyses. We used this same strategy to determine the effect of excluding studies that used adjusted-dose low-molecular-weight heparin because previous meta-analyses have included these studies. Because the natural history of calf venous thrombosis differs from that of proximal venous thrombosis (29, 30), we asked authors of studies that included participants with distal thrombosis to provide data on thromboembolic recurrences and mortality rates for the group of participants with proximal disease. We then performed secondary analyses using these data. To explore the influence of study-level factors on treatment effect, we used a series of log-linear models, each fit by maximum likelihood estimation. The goodness of fit of these models was compared by using analysis of deviance, a likelihood ratio test analogous to analysis of variance (31). These models were constructed to quantify the amount of variation in study outcomes and to determine whether statistically significant variation could be explained by one or more study-level factors, such as the timing of warfarin administration. Role of the Funding Source The funding source had no role in the collection, analysis, or interpretation of data or in the decision to seek publication. Results Study Identification and Selection Our search identified 966 potentially relevant studies. We excluded 920 studies after scanning their titles and abstracts. Two potentially eligible non-English-language articles were excluded from our analysis (32, 33). These trials examined bleeding complications in 129 persons but did not evaluate thromboembolic recurrences or mortality rates over 3 to 6 months. We retained 37 articles and 7 abstracts for further evaluation. Three abstracts were subsequently published as full reports (34-36). The other 4 abstracts were excluded because the authors did not provide complete details (37-40), because unfractionated heparin was not dose-adjusted (37), or because heparin treatment was continued for 3 months (38). Of the 37 remaining articles, 11 met inclusion criteria for each of the three major outcomes. Twenty-six studies were excluded for the following