Background: Outcome measures in randomized controlled trials (RCTs) can be classified as patient-important, surrogate and composite outcomes. Venous thromboembolism (VTE) prophylaxis trials often use surrogate or composite outcome measures, often involving radiographically detected and clinically asymptomatic VTE. The clinical relevance of such outcomes is controversial.
Objective: To establish the prevalence of surrogate outcome measures in VTE prophylaxis trials.
Methods: A comprehensive search of MEDLINE, Embase and Cochrane (CENTRAL) databases from January 2000 to October 2020 was conducted. Any English-language VTE prophylaxis RCT with n>150 was included. Baseline characteristics, outcome measure, acknowledgement of limitations, and presence of VTE vs bleeding risk discussions were recorded. Binary logistic regression analysis was done to assess the relationship of impact factor, citation count, and sample size with surrogate outcome use.
Results: 209 studies were included. 170 (81%) studies used a surrogate outcome measure. Of these studies, 34 (20%) acknowledged this as a potential limitation and 152 (89%) discussed bleeding vs thrombosis risk. There was no statistically significant relationship between citation count (ꞵ1OR=0.99; 95%CI=0.99-1.00; p=0.248) or sample size (ꞵ1OR=0.99, 95%CI=0.99-1.00, p=0.320) and use of a surrogate outcome compared with use of a clinical outcome. There was a statistically significant relationship between increased impact factor and use of a surrogate outcome (ꞵ1OR=0.98, 95%CI=0.97-0.99, p<0.05).
Conclusion: Use of surrogate outcomes is prevalent in VTE prophylaxis literature and is rarely acknowledged. While using patient-important outcome measures may not be feasible in all settings, we recommended clinicians acknowledge the limitation of surrogate outcomes, especially when discussing bleeding vs thrombosis risk.