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

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 Low-molecular-weight heparin has greatly simplified the initial management of deep venous thrombosis because it is at least as effective and safe as unfractionated heparin and can be administered subcutaneously at fixed doses without laboratory monitoring (1). These features allow a substantial proportion of patients with deep venous thrombosis to be treated at home without being admitted, improving their quality of life and reducing health care costs (2, 3). The role of fixed-dose low-molecular-weight heparin as therapy for patients with acute pulmonary embolism is less certain. Many clinicians continue to treat pulmonary embolism with dose-adjusted intravenous unfractionated heparin because of concern that patients with pulmonary embolism are at higher risk for fatal outcomes than are those who present with deep venous thrombosis alone, and because evidence that low-molecular-weight heparin is effective and safe for the treatment of pulmonary embolism is believed to be insufficient (4). However, deep venous thrombosis and pulmonary embolism share a common pathophysiologic process and risk factors, and postmortem studies indicate that the majority of patients with pulmonary embolism also have thrombosis involving the leg veins (5). Moreover, several randomized trials have suggested that patients with symptomatic pulmonary embolism (6, 7) or asymptomatic pulmonary embolism in the context of symptomatic deep venous thrombosis (8, 9) can be treated with low-molecular-weight heparin instead of unfractionated heparin. Consequently, pulmonary embolism and deep venous thrombosis are now increasingly recognized as different manifestations of the same disease process, collectively known as venous thromboembolism, and may also reasonably be expected to respond similarly to treatment with low-molecular-weight heparin. To further clarify the efficacy and safety of low-molecular-weight heparin for the initial treatment of pulmonary embolism, we performed a meta-analysis of all randomized trials that compared fixed-dose low-molecular-weight heparin with dose-adjusted intravenous unfractionated heparin for this indication. We included trials that enrolled patients with symptomatic pulmonary embolism or asymptomatic pulmonary embolism in the context of symptomatic deep venous thrombosis. The primary outcome was recurrent symptomatic venous thromboembolism, includ ing deep venous thrombosis and pulmonary embolism, at the end of treatment. Secondary outcomes were recurrent symptomatic venous thromboembolism at 3 months, all-cause mortality, and major and minor bleeding. Methods A protocol was prospectively developed in which the specific objectives, criteria for study selection, the approach to assessing study quality, primary and secondary outcomes, and statistical methods were defined. Study Identification We attempted to identify all relevant published and unpublished unconfounded randomized trials that compared fixed-dose low-molecular-weight heparin with dose-adjusted intravenous unfractionated heparin for the initial treatment of pulmonary embolism. We searched electronic databases (MEDLINE and EMBASE) and the Cochrane Library to 1 August 2003 by using the terms thrombosis, thromboembolism, pulmonary embolism, randomized, controlled trial, controlled clinical trial, and random, in combination with generic and trade names of individual preparations of low-molecular-weight heparin. We manually searched the bibliographies of journal articles to locate additional studies, reviewed abstracts from major international meetings, and contacted manufacturers of low-molecular-weight heparin agents to learn of unpublished studies. Relevance was assessed by using a hierarchical approach based on title, abstract, and published or unpublished articles. Study Selection Two investigators independently evaluated studies for possible inclusion, and disagreements were resolved by discussion. To be included, studies had to be properly randomized; include patients with objectively diagnosed symptomatic pulmonary embolism or objectively diagnosed asymptomatic pulmonary embolism in addition to symptomatic deep venous thrombosis; compare fixed-dose low-molecular-weight heparin with dose-adjusted intravenous unfractionated heparin; and use objective methods to assess one or more clinical outcomes, including recurrent symptomatic venous thromboembolism, major bleeding, minor bleeding, and death. The type of low-molecular-weight heparin preparation, dose, duration of treatment, or duration of follow-up was not used to determine eligibility of studies for inclusion. Assessment of Study Quality We used the study-quality criteria of Schultz and colleagues (10) to evaluate the studies included in our meta-analysis. These criteria include proper generation of the treatment allocation sequence, proper concealment of the allocation sequence, blinding of the patient and the investigator who assessed clinical outcomes to treatment allocation, and completeness of follow-up. Data Extraction Two investigators independently extracted data on study design, study quality, and the following efficacy and safety outcomes at the end of treatment and at 3 months: symptomatic venous thromboembolism, death, major bleeding, and minor bleeding. We accepted the investigators' definitions of deep venous thrombosis, pulmonary embolism, and major and minor bleeding. The data abstracted for each trial were confirmed by reviewer consensus and were sent to the first or corresponding author for verification. Missing data were requested from the investigators or sponsoring company at that time. Statistical Analysis We used a fixed-effects model based on the MantelHaenszel method for combining results from the individual trials (11). This model is also known as an assumption-free model because it does not assume that included studies are a random sample of the universe of studies and it provides a pooled estimate of treatment effect that is conditional on the available trial data. We calculated the odds ratio and 95% CIs. The test of heterogeneity was calculated by using the MantelHaenszel method. All statistical calculations were performed by using Comprehensive Meta Analysis software, version 1.0. 23 (Biostat, Englewood, New Jersey). We performed sensitivity analyses to further establish the robustness of our results. To identify any study that may have exerted a disproportionate influence on the summary treatment effect, we deleted studies one at a time. We examined the effect of excluding lower-quality studies (open-label studies and those with incomplete follow up) from the analysis. An inverted funnel plot of treatment effect versus study precision was created for the primary outcome to detect publication bias (12), a technique that may be helpful to determine whether additional small studies may have been conducted but not published because of unfavorable or negative results. Finally, results obtained by using a fixed-effects model were compared with those obtained by using a random-effects model. Results Study Selection Figure 1 shows the process of study selection. We identified 551 potentially eligible citations. We excluded 517 citations after scanning their titles and abstracts, leaving 34 citations for further evaluation. We obtained the completed but unpublished manuscript for one abstract (13) from the authors. We excluded 18 studies in which low-molecular-weight heparin was administered intravenously (14, 15), the dose of low-molecular-weight heparin was adjusted according to the results of laboratory monitoring (16, 17), unfractionated heparin was administered subcutaneously (18, 19), the duration of treatment with 2 therapies was unequal (20), or patients presenting with deep venous thrombosis were included but objective diagnostic testing was not done to screen for associated asymptomatic pulmonary embolism (21-31). Of the 16 remaining studies, one reported outcome data on the subgroup of patients with pulmonary embolism (8) from a study that had previously been published (32). Contact with the authors of another study revealed that study treatment was allocated by using alternate odd and even numbers (33). These 2 studies were excluded. Two additional studies were excluded because we could not obtain separate outcome data for patients with pulmonary embolism despite contact with the investigators and sponsoring pharmaceutical companies (34, 35). Thus, 12 studies were available for inclusion (6, 9, 13, 32, 34, 36-42). Figure 1. Process of study selection Study Design Table 1 shows the designs of the studies. The majority of trials were small, and only 4 trials included 200 or more patients (6-9, 32). Six studies included patients with symptomatic pulmonary embolism (6, 7, 13, 38-40), and 2 included only patients with symptomatic deep venous thrombosis but screened all patients for associated asymptomatic pulmonary embolism at baseline (36, 37). Four studies included patients with symptomatic deep venous thrombosis or pulmonary embolism (9, 32, 41, 42). No trial stratified randomization by the presence or absence of asymptomatic pulmonary embolism at baseline or included patients with massive pulmonary embolism. Six low