Russell D. Hull

Subcutaneous Low-Molecular-Weight Heparin Compared with Continuous Intravenous Heparin in the Treatment of Proximal-Vein Thrombosis

Abstract Background. Low-molecular-weight heparin has a high bioavailability and a prolonged half-life in comparison with conventional unfractionated heparin. Limited data are available for low-molecular-weight heparin as compared with unfractionated heparin for the treatment of deep-vein thrombosis. Methods. In a multicenter, double-blind clinical trial, we compared fixed-dose subcutaneous low-molecular-weight heparin given once daily with adjusted-dose intravenous heparin given by continuous infusion for the initial treatment of patients with proximal-vein thrombosis, using objective documentation of clinical outcomes. Results. Six of 213 patients who received low-molecular-weight heparin (2.8 percent) and 15 of 219 patients who received intravenous heparin (6.9 percent) had new episodes of venous thromboembolism (P = 0.07; 95 percent confidence interval for the difference, 0.02 percent to 8.1 percent). Major bleeding associated with initial therapy occurred in 1 patient receiving low-molecular-weight h...

Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

D-Dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism: A Systematic Review

Context Clinicians may not know which d-dimer assay is best for diagnosing deep venous thrombosis (DVT) or pulmonary embolism (PE). Contribution This meta-analysis summarizes data from 78 prospective studies that compared results of different d-dimer assays with findings of objective tests (for example, compression ultrasonography, venography, lung scanning) in patients with suspected DVT or PE. Enzyme-linked immunosorbent assays (ELISAs) had the best sensitivity (about 95%) and negative likelihood ratios (about 0.1) for excluding DVT and PE. None of the assays had positive likelihood values that greatly increased the certainty of diagnosis. Implications Negative ELISA results are strong evidence against DVT or PE. The Editors Tests for d-dimer to exclude venous thromboembolic disease have been available since the 1980s (1). Hundreds of original studies, reviews, commentaries, and technical notes related to d-dimer as a diagnostic aid have been published. Even with this extensive literature, the role of d-dimer in the diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) remains unclear. This lack of clarity is due in part to the multiple d-dimer assays that are available (Appendix Table 1), availability of central laboratory and point-of-care testing, and concerns about differing sensitivities and variability of the assays (1). In 1998, the American College of Chest Physicians Consensus Panel on Pulmonary Embolism called for more evaluation of the utility of d-dimer (2). In 1999, a Clinical Practice Guideline of the American Thoracic Society also called for additional outcome studies to further define the role of rapid bedside assays of d-dimer (3). As recently as 2000, investigators argued that the whole-blood agglutination test with d-dimer is not validated for clinical use for the exclusion of DVT (4). Although several useful reviews of the topic exist (1, 3, 5), none in recent years have comprehensively reviewed the world literature in an effort to summarize the accumulated published experience with d-dimer testing. Given continuing uncertainty about d-dimer testing, we performed a systematic review of the literature to assess the sensitivity and specificity of the d-dimer assays and the variability of those measures among studies for diagnosing DVT and PE. The comparative findings among the differing d-dimer assays provide both the laboratory pathologist and clinician with a practical pathway for translating clinical research into practice. Methods We used several sources to guide our review processes, including recommendations by Lijmer and colleagues concerning avoidance of bias in studies of diagnostic tests (6), the Standards for Reporting Diagnostic Accuracy (STARD) statement (7, 8), and guidelines for meta-analyses of observational studies in epidemiology (9). Study Identification We attempted to identify all published trials in all languages that used d-dimer to exclude PE or DVT on the basis of objective diagnostic tests. Studies were identified by searching PubMed from 1983 to January 2003 and EMBASE from 1988 to January 2003. All searches used the key words d -dimer, PE, and DVT. We augmented our searches by manually reviewing the reference lists of all original articles and all review articles. This was done by 2 of the authors working together. Abstracts were excluded. Study Eligibility At least 2 authors evaluated each study for inclusion. Any disagreements were resolved by discussion. Authors were not blinded to journal, author, or institution. Studies were included if they met all of the following criteria: 1) A specific statement was made about whether PE or DVT (not the inclusive term thromboembolic disease) was being diagnosed; 2) the diagnosis of PE or DVT was based on objective tests; 3) studies were performed prospectively; 4) participants were recruited consecutively; 5) the population studied included a broad spectrum of patients; 6) results of d-dimer and the diagnostic tests for PE and DVT were interpreted independently; 7) the participants studied were suspected of having PE or DVT, and all studies included patients with and without disease; 8) the decision to perform the reference diagnostic test was made independently of the d-dimer result; 9) test descriptions were sufficiently detailed to permit replication; 10) the cutoff value for a negative d-dimer test result was stated unless qualitative tests were used; and 11) sensitivity and specificity or the raw data for these calculations were presented. We labeled studies that did not meet the third, fourth, or tenth inclusion criteria as tier 3 studies and included them in sensitivity analyses. We categorized studies that met all inclusion criteria into 2 tiers. Tier 1 included studies that compared an enzyme-linked immunosorbent assay (ELISA) and at least one other d-dimer assay. Tier 2 included the tier 1 studies and all other studies that met all inclusion criteria. Data Extraction Two authors collected data on the following study-level factors: 1) the d-dimer assay used in the study, 2) the cutoff value below which disease was considered to be absent, and 3) whether d-dimer was used to exclude PE or DVT. At least 2 authors confirmed the values for sensitivity and specificity. Statistical Analysis Sensitivities reflect the proportion of patients with disease who had a positive d-dimer result, while specificities reflect the proportion of patients without disease who had a negative d-dimer result, depending on cutoff level. Values for the likelihood ratio (the multiplicative factor for converting pretest to post-test disease probabilities) associated with positive test results were obtained by the following formula: sensitivity/(1 corresponding specificity). This formula provided likelihood ratios arising from negative test results. Primary analysis was restricted to the 500-ng/mL cutoff because that was the most commonly used value. On the basis of the varying array of assays examined in individual studies and our anticipation of important between-study heterogeneity, we applied a linear mixed-model approach (10) to jointly analyze the proportions of positive test results in the disease and nondisease samples (that is, true-positive and false-positive rates). Similar models have been applied to Bayesian meta-analysis of receiver-operating characteristic curves (11). The main explanatory term in the model was a fixed effect reflecting distinct positive response rates for each combination of assay and population. To allow for variability in assay performance that might arise from idiosyncratic features of patient samples, such as spectrum of disease severity, and other aspects of study context, such as laboratory procedure, we incorporated 3 random-effects terms corresponding to assay nested within patient group (disease/nondisease) nested within study. Residual variances were assumed to follow the standard binomial form depending on underlying proportion and sample size. Applying restricted maximum likelihood, we obtained population average estimates for sensitivity and specificity, which were later combined to provided estimated likelihood ratios. Overall, the estimates did not differ substantially from conventional sample-size weighted averages, although the associated standard errors were increased, reflecting underlying between-study heterogeneity. The joint statistical significance of overall differences was assessed by using likelihood-based Wald tests. Pairwise differences between estimates were assessed on the basis of the model-based standard errors without adjustment for multiple comparisons. Significant pairwise differences should be interpreted with caution when the Wald test is not significant. Confidence limits are derived from asymptotic standard errors; asymmetric intervals for likelihood ratios reflect the application of likelihood theory to logarithmically transformed estimates. Values for the sensitivity and specificity for the different studies and test types were examined graphically by use of boxplots. The range between the upper and lower quartiles of the values for each assay provides a measure of between-study variability associated with the assay. Sensitivity analyses were conducted by adding the 30 studies that did not meet one or more of the 3 inclusion criteria previously mentioned (tier 3 analysis) and by analyzing sensitivity and specificity at the 250-ng/mL and 1000-ng/mL cutoffs. All analyses were conducted by using S-PLUS, version 6.1.2, 2002 (Insightful Corp., Seattle, Washington) (12). Data Synthesis Figure 1 summarizes our search. We initially identified 513 potentially relevant reports. Thirty-one studies (13-43) were included; they met a priori inclusion criteria and compared 2 or more assays, including an ELISA (tier 1 analysis). An additional 47 studies (44-90) were also included; they did not have a comparative ELISA but met the a priori inclusion criteria evaluating a d-dimer assay. The 47 studies combined with the 31 studies provided a study sample of 78 studies (tier 2 analysis). Thirty additional studies (91-120) that did not meet one or more inclusion criteria were included in the sensitivity, or tier 3, analysis, which also included the 78 studies in the tier 2 analysis. Figure 1. Reports evaluated for inclusion in the review. Appendix Tables 2 and 3 list the d-dimer assays that were evaluated, patient characteristics, and the objective diagnostic reference test that was used for patients with clinically suspected DVT (49 studies) and clinically suspected PE (31 studies). All studies met the 11 criteria for inclusion listed in the Methods section. There was a total of 78 studies (2 studies [60, 71] gave data for patients with PE and DVT separately in the same article). In the various studies, prevalence of DVT ranged from 20% to 78% (overall prevalence, 36%), and the prevalence of PE ranged from 8% to 62% (overall prevalence, 25%). Sixteen studies of DVT used comp

Warfarin Sodium versus Low-Dose Heparin in the Long-Term Treatment of Venous Thrombosis

Acute deep-vein thrombosis is usually treated with intravenous heparin for a number of days, then with oral anticoagulants for weeks to months. We have compared adjusted-dose warfarin sodium with fixed low-dose subcutaneous heparin in the prevention of recurrent deep-vein thrombosis. Sixty-eight patients with acute deep-vein thrombosis confirmed by venography were treated with intravenous heparin and then randomized to secondary prophylaxis. Nine of 35 patients receiving subcutaneous heparin, but none of 33 receiving warfarin sodium, had new episodes of objectively documented venous thromboembolism (P = 0.001). Seven patients on warfarin sodium experienced bleeding complications (of which four were major), as compared with no patients receiving subcutaneous heparin (P less than 0.005). Thus, adjusted-dose warfarin sodium is more effective than low-dose subcutaneous heparin in preventing recurrent venous thromboembolism, but its use is accompanied by a significant risk of bleeding.

A Randomized Controlled Trial of a Low-Molecular-Weight Heparin (Enoxaparin) to Prevent Deep-Vein Thrombosis in Patients Undergoing Elective Hip Surgery

There is experimental evidence that low-molecular-weight fractions of heparin are as effective as the standard form but cause less bleeding. We therefore performed a double-blind, randomized trial comparing PK10169 low-molecular-weight heparin with placebo for the prevention of venous thrombosis in patients undergoing elective hip surgery. Prophylactic treatment with a fixed dose was begun postoperatively and continued for 14 days. Fifty patients in each treatment group underwent surveillance with [125I]fibrinogen leg scanning and impedance plethysmography. In the first 24 patients, venography was performed only if either surveillance test was positive. Because the rate of venous thrombosis detected in those patients was unexpectedly low, venography was requested in the remaining 76 patients, even if the screening tests were negative. In this latter group, venous thrombosis occurred in 4 patients (10.8 percent) given PK10169 heparin and 20 patients (51.3 percent) given placebo (P = 0.0002); the corresponding rates for proximal-vein thrombosis were 5.4 percent and 23.1 percent, respectively (P = 0.029). In the entire group of 100 patients, venous thrombosis occurred in 12 percent of those given PK10169 heparin and 42 percent of those given placebo (P = 0.0007), and the corresponding rates for proximalvein thrombi were 4 percent and 20 percent, respectively (P = 0.014). The observed hemorrhagic rate was 4 percent in each treatment group. We conclude that prophylaxis with fixed-dose PK10169 heparin is effective and safe for patients undergoing elective hip replacement.

Heparin for 5 Days as Compared with 10 Days in the Initial Treatment of Proximal Venous Thrombosis

It is common practice to begin anticoagulant treatment of deep-vein thrombosis with a 10-day course of intravenous heparin, with warfarin added on day 5 to 10 and continued for several months. We performed a randomized, double-blind trial comparing a shorter course of continuous intravenous heparin (5 days, with warfarin sodium begun on the first day) with the conventional 10-day course of heparin (with warfarin sodium begun on the fifth day) in the initial treatment of 199 patients with acute proximal venous thrombosis documented by venography. The frequency of objectively documented recurrent venous thromboembolism was low and essentially the same in the two groups (7.1 percent in the short-course group vs. 7.0 percent in the long-course group). Because the observed difference between the groups was 0.1 percent in favor of the long-course group, it is unlikely (P less than 0.05) that a true difference in favor of this group would be greater than 7.5 percent; the difference could be as much as 7.3 percent in favor of the short-course group. Major bleeding episodes were infrequent, and the rate was similar in both groups. We conclude that a five-day course of heparin is as effective as a 10-day course in treating deep venous thrombosis. Furthermore, using the shorter course would permit earlier discharge from the hospital and thus offer substantial cost savings.

A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation.

BACKGROUND Deep-vein thrombosis is a potentially life-threatening complication of total hip or knee replacement. There are few data on the effectiveness and safety of warfarin as compared with low-molecular-weight heparin as prophylaxis against this problem. METHODS We therefore performed a randomized, double-blind trial in 1436 patients to evaluate the effectiveness and safety of low-molecular-weight heparin (given subcutaneously once daily) as compared with adjusted-dose warfarin to prevent venous thrombosis after hip or knee replacement. Treatment with the drugs was started postoperatively. The primary end point was deep-vein thrombosis as detected by contrast venography (performed a mean of 9.4 days after surgery in each group). RESULTS Among the 1207 patients with interpretable venograms, 231 of 617 patients (37.4 percent) in the warfarin group and 185 of 590 patients (31.4 percent) in the low-molecular-weight-heparin group had deep-vein thrombosis (P = 0.03). The reduction in risk with low-molecular-weight heparin as compared with warfarin was 16 percent, and the absolute difference in the incidence of venous thrombosis was 6 percent in favor of low-molecular-weight heparin (95 percent confidence interval, 0.8 to 11.4 percent). The incidence of major bleeding was 1.2 percent (9 of 721 patients) in the warfarin group and 2.8 percent (20 of 715 patients) in the low-molecular-weight-heparin group (P = 0.04), and the absolute difference was 1.5 percent in favor of warfarin (95 percent confidence interval, 0.1 to 3.0 percent). CONCLUSIONS Our data demonstrate that the small reduction in the incidence of venous thrombosis with low-molecular-weight heparin, as compared with warfarin, was offset by an increase in bleeding complications. Although the use of low-molecular-weight heparin is simpler, because it is administered subcutaneously without the need for monitoring, it may be more costly than warfarin. Warfarin is inexpensive, but the overall cost of its use is increased by the need to monitor the intensity of anticoagulation. At this time it is unclear which of these approaches is the most cost effective.

Adjusted Subcutaneous Heparin versus Warfarin Sodium in the Long-Term Treatment of Venous Thrombosis

Abstract Previously, we compared fixed low doses of heparin with adjusted doses of warfarin for the long-term treatment of venous thrombosis; in that study low-dose heparin was ineffective in preventing recurrence in patients with proximal-vein thrombosis. We have now completed a randomized trial comparing adjusted doses of heparin and of warfarin for prevention of recurrent venous thromboembolism in patients with proximal-vein thrombosis. One hundred six consecutive patients with acute proximal-vein thrombosis confirmed by venography were treated with intravenous heparin and then randomized to secondary prophylaxis. Two of 53 patients receiving heparin, as compared with one of 53 receiving warfarin, had new episodes of objectively documented venous thromboembolism. Nine patients taking warfarin had bleeding complications (which were major in three patients), as compared with one patient taking heparin (P = 0.008). Our data indicate that adjusted-dose subcutaneous heparin therapy provides an effective alt...

Rivaroxaban for thromboprophylaxis in acutely ill medical patients.

BACKGROUND The clinically appropriate duration of thromboprophylaxis in hospitalized patients with acute medical illnesses is unknown. In this multicenter, randomized, double-blind trial, we evaluated the efficacy and safety of oral rivaroxaban administered for an extended period, as compared with subcutaneous enoxaparin administered for a standard period, followed by placebo. METHODS We randomly assigned patients 40 years of age or older who were hospitalized for an acute medical illness to receive subcutaneous enoxaparin, 40 mg once daily, for 10±4 days and oral placebo for 35±4 days or to receive subcutaneous placebo for 10±4 days and oral rivaroxaban, 10 mg once daily, for 35±4 days. The primary efficacy outcomes were the composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 10 (noninferiority test) and up to day 35 (superiority test). The principal safety outcome was the composite of major or clinically relevant nonmajor bleeding. RESULTS A total of 8101 patients underwent randomization. A primary efficacy outcome event occurred in 78 of 2938 patients (2.7%) receiving rivaroxaban and 82 of 2993 patients (2.7%) receiving enoxaparin at day 10 (relative risk with rivaroxaban, 0.97; 95% confidence interval [CI], 0.71 to 1.31; P=0.003 for noninferiority) and in 131 of 2967 patients (4.4%) who received rivaroxaban and 175 of 3057 patients (5.7%) who received enoxaparin followed by placebo at day 35 (relative risk, 0.77; 95% CI, 0.62 to 0.96; P=0.02). A principal safety outcome event occurred in 111 of 3997 patients (2.8%) in the rivaroxaban group and 49 of 4001 patients (1.2%) in the enoxaparin group at day 10 (P<0.001) and in 164 patients (4.1%) and 67 patients (1.7%) in the respective groups at day 35 (P<0.001). CONCLUSIONS In acutely ill medical patients, rivaroxaban was noninferior to enoxaparin for standard-duration thromboprophylaxis. Extended-duration rivaroxaban reduced the risk of venous thromboembolism. Rivaroxaban was associated with an increased risk of bleeding. (Funded by Bayer HealthCare Pharmaceuticals and Janssen Research and Development; MAGELLAN ClinicalTrials.gov number, NCT00571649.).

Extended Out-of-Hospital Low-Molecular-Weight Heparin Prophylaxis against Deep Venous Thrombosis in Patients after Elective Hip Arthroplasty: A Systematic Review

The use of accurate, objective venographic testing to detect deep venous thrombosis in patients who undergo hip arthroplasty has led to randomized trials of various prophylactic regimens against venous thromboembolism (123). The need for in-hospital prophylaxis has been firmly established (24, 25) and accepted in clinical practice. Evidence-based medicine guidelines (26) based on venographic end points recommend low-molecular-weight heparin (LMWH) prophylaxis or warfarin prophylaxis for 7 to 10 days in patients who undergo elective hip surgery (25). These guidelines are considered a grade 1A recommendation, which indicates a strong recommendation for a therapy that has a clear benefit; the recommendation is based on randomized clinical trials that do not have important limitations and that can apply to most patients in most circumstances without reservation (26). Recent surveys indicate that more than 90% of patients who have undergone elective hip surgery have received thromboprophylaxis (27, 28). The results of randomized trials in Europe indicate the need for extended out-of-hospital prophylaxis in patients undergoing hip arthroplasty (2934). In contrast, on the basis of relatively low rates of symptomatic venous thromboembolism observed in descriptive studies in North America with long-term follow-up, investigators have inferred that extended prophylaxis is not required (3539). For these reasons, the reports of the Fifth (24) and Sixth (25) American College of Chest Physicians Consensus Conferences stated that extended out-of-hospital prophylaxis by using LMWH may offer additional protection. This is a 2A recommendation because of uncertainty regarding the riskbenefit ratio (24) and cost-effectiveness (25). A grade 2A recommendation indicates unclear benefit based on randomized clinical trials without important limitations and is an intermediate-strength recommendation (26). A possible interpretation of the North American data (3539) is that extended prophylaxis is unnecessary for patients in the United States and Canada because of differences in clinical practice, a shorter length of hospital stay, and earlier patient ambulation compared with Europe. A recent epidemiologic study (27) used a linked hospital discharge database provided by the State of California to report the outcomes in 19 586 patients undergoing total-hip arthroplasty and 24 059 patients undergoing knee arthroplasty. Of the patients having elective hip surgery who had symptomatic venous thromboembolism, the median time of the event was postoperative day 17, whereas the median time in patients having knee surgery was postoperative day 7; most patients (>90%) received in-hospital prophylaxis. These findings strongly suggest a need for extended out-of-hospital prophylaxis in patients undergoing total-hip replacement but not for patients undergoing total-knee replacement. Given the uncertainty about the need for extended prophylaxis, we performed a systematic review to provide clinicians with a practical pathway for translating clinical research into practice. Methods To ensure high methodologic quality, we adhered to the 15 criteria for systematic review outlined by McAlister and colleagues (40, 41). The first 10 criteria assess methodologic rigor, and the last 5 criteria assess the scientific basis of treatment recommendations (40). We also adhered to the QUOROM (Quality of Reporting of Meta-analyses) guidelines (42) for the reporting of meta-analyses of randomized trials. We systematically identified published and unpublished articles for inclusion in this analysis, described variations in study design and execution, evaluated study quality (43), and quantified the relative benefits of extended prophylaxis with LMWH (44). We excluded studies that did not use venography to assess the presence or absence of deep venous thrombosis because previous studies have shown that noninvasive tests, including duplex ultrasonography, are relatively insensitive for detecting thrombosis in patients who have undergone hip replacement (25). Study Identification We attempted to identify all published and unpublished randomized trials that compared extended prophylaxis with LMWH versus out-of-hospital placebo in patients undergoing hip arthroplasty. A strategy was developed for locating all studies in the PubMed and MEDLINE databases that were published between January 1976 and May 2001; the search was not restricted to English-language journals. We augmented our MEDLINE search by manually reviewing the reference lists of original articles and review articles. We also reviewed abstracts in conference proceedings and through the Cochrane Library Database and contacted investigators and pharmaceutical companies. Study Eligibility Two investigators independently evaluated studies for inclusion in the systematic review, and any disagreements were resolved by discussion between these two investigators. Investigators were not blinded to journal titles, author names, or institutional affiliations. Studies were included if they 1) enrolled patients undergoing elective hip arthroplasty, 2) randomly assigned participants to treatment groups, 3) investigated the extended posthospital discharge efficacy of once-daily subcutaneous LMWH compared with out-of-hospital placebo for prevention of deep venous thrombosis, 4) objectively documented the presence or absence of all episodes of deep venous thrombosis and proximal venous thrombosis by using bilateral ascending contrast venography, and 5) used objective methods for assessing bleeding complications (2932, 45, 46). Abstracts that reported full methods and results were eligible for inclusion. Deep venous thrombosis was defined as constant intraluminal filling defects in the deep veins; proximal venous thrombosis was defined as constant intraluminal filling defects in the popliteal deep veins or in the more proximal deep veins. Data Extraction One study investigator collected data on the following study-level factors: 1) the type of LMWH prophylaxis used, 2) whether a high-risk dose, approved by a regulatory affairs authority, was used, 3) the frequency of administration of LMWH, 4) the length of in-hospital stay, 5) the time interval after surgery when venography was performed [in days], and 6) venographic findings. For the last factor, we noted new out-of-hospital findings on venography or combined in-hospital and out-of-hospital findings on venography; where both findings were reported, we analyzed new out-of-hospital findings, which were more conservative and more recent. Two investigators independently extracted data on the major outcomes, which were the frequency of 1) all episodes of deep venous thrombosis, 2) proximal venous thrombosis, 3) symptomatic deep venous thrombosis and pulmonary embolism, and 4) major-bleeding complications. They also recorded data on other variables, including death, minor bleeding, wound hematomas, and thrombocytopenia. After the two investigators made their respective independent selection of studies for inclusion in the analysis, we compared their selections and calculated the percentage of agreement between them and the coefficient (47). Investigator disagreements were resolved by discussion. Assessment of Study Quality We assessed the quality and strength of each study by examining four key issues: 1) true randomization by using a random-numbers table or a computer program; 2) the masking of the allocation sequences from the investigators, staff, and patients involved in the study; 3) double-blinding [45]; and 4) the proportion of patients with successful (adequate) venography. One investigator extracted these data from the primary studies. When details were not reported, we requested additional information from the authors. Data Synthesis and Statistical Analysis For each of the major outcomes, we calculated summary treatment effects as the relative risk and the number needed to treat for benefit (NNTB) to prevent one thromboembolic event. The relative risk was used as the primary measure of treatment effect. We considered a P value less than 0.05 to be statistically significant for all statistical tests. Analyses were performed by using the metan procedure (48) of Stata software, release 6.0 (Stata Corp., College Station, Texas). To assess the validity of combining results from individual studies, we used the MantelHaenszel test for statistical heterogeneity (49). The outcome values were combined in both fixed-effects and random-effects models to estimate treatment effects on outcomes for all the studies. The relative risk ratios were consistent among studies for the treatment effect of preventing venographically documented deep venous thrombosis (all episodes and cases of proximal deep venous thrombosis); however, the 95% CIs for the relative risk ratios within studies were relatively wide. Therefore, we combined the data to provide more precise estimates of relative risk and NNTB. Results for NNTB were based on random-effects analysis of risk. Sensitivity Analysis We performed a sensitivity analysis for each of the three major outcomes. To uncover possible publication bias, we created inverted funnel plots for the major outcomes by plotting odds ratios against the sample size for each study (50). Moreover, to identify any studies that exerted a disproportionate influence on the summary treatment effect, we performed repeated calculations in which the data from each individual study were deleted, one at a time. Trials that met all inclusion criteria except for onethe use of bilateral ascending venography to assess end points at the end of the out-of-hospital study intervalwere included in a secondary meta-analysis of symptomatic venous thromboembolism and major bleeding end points. Results Study Identification and Selection Our search strategies identified 206 potentially relevant studies. After an initial scanning of titles and abstracts, we excluded 184 studies: 160 studies did