Methodological issues in trials assessing primary prophylaxis of venous thrombo-embolism

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Abstract
Aims Many trials have been conducted to assess the efficacy of various strategies in the prevention of venous thrombo-embolism (VTE). Some of these trials have been subject to methodological criticisms. We aimed to assess the methodological issues raised by VTE trials. Methods and results We searched MEDLINE and the Cochrane Central Register of Controlled Trials for articles assessing primary thromboprophylaxis published between 1994 and 2003 in 60 general medical and specialty journals. A total of 77 articles were analysed by two independent reviewers using a list of items. No primary endpoint was defined in 20% of trials. Although the primary endpoint was collected before day 15 in 75% of trials, there were ≥20% missing data in 56% of articles and ≥30% in 24.2% of articles. The rate of missing data was 23.7±9.7% in studies using venography-detected deep-vein thrombosis as an endpoint compared with 5.6±6.0% in studies using other endpoints. Among the 47 superiority trials, 27 (57.4%) reported an intention-to-treat (ITT) analysis, but only 10 (21.3%) reported an analysis that complied with this principle. These results were consistent when limiting the analysis to articles published in high-impact journal (impact factor more than 5). Conclusion Recent randomized controlled trials assessing prophylactic regimens in VTE have important methodological limitations in terms of primary endpoints, missing data, and compliance with the ITT principle. These methodological shortcomings should be addressed when planning future trials.