Randomised controlled trials for the prevention of venous thromboembolism in critically ill patients: A systematic review of sample size methodologies

Abstract

Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, contributes significantly to morbidity and mortality in critically ill patients. This increased incidence is influenced by factors such as indwelling central venous catheters, continuous sedation, and vasoactive infusions, in addition to traditional VTE risk factors such as immobility. Optimal VTE prophylaxis remains uncertain owing to significant variability with regard to differences across existing randomized controlled trials (RCTs) in terms of patient populations, types and dosing of prophylactic interventions, and definitions of VTE outcomes. RCTs conducted on critically ill patients are often limited by over-optimistic estimates of baseline event rates and potential treatment benefit. We conducted a systematic review to evaluate the described sample size methodologies and justification amongst VTE-prevention RCTs for critically ill patients. We searched MEDLINE and Embase from inception until 9 September 2024, and included 12 RCTs enrolling 9154 patients. Sample sizes ranged from 36 to 3746 participants. Only six studies met their recruitment targets, while four did not report a sample size calculation. Among the seven studies that reported an estimated control event rate, only one met that estimate. No studies achieved their planned absolute risk reduction, and only one met its relative risk reduction target. Prognostic enrichment strategies were employed in 41.6% of trials, while predictive enrichment was rarely used. These findings suggest that intensive care unit VTE prophylaxis trials frequently overestimate baseline risk and treatment effect size, contributing to underpowered studies and potential premature abandonment of promising interventions. Future trials should incorporate enrichment strategies and justify assumptions based on clinical relevance and patient-centred outcomes.