Abstract
BackgroundThis a priori statistical analysis plan describes the analysis for CRISTAL.MethodsCRISTAL (cluster-randomised, crossover, non-inferiority trial of aspirin compared to low molecular weight heparin for venous thromboembolism prophylaxis in hip or knee arthroplasty, a registry nested study) aims to determine whether aspirin is non-inferior to low molecular weight heparin (LMWH) in preventing symptomatic venous thromboembolism (VTE) following hip arthroplasty (HA) or knee arthroplasty (KA). The study is nested within the Australian Orthopaedic Association National Joint Replacement Registry. The trial was commenced in April 2019 and after an unplanned interim analysis, recruitment was stopped (December 2020), as the stopping rule was met for the primary outcome.The clusters comprised hospitals performing > 250 HA and/or KA procedures per annum, whereby all adults (> 18 years) undergoing HA or KA were recruited. Each hospital was randomised to commence with aspirin, orally, 85–150 mg daily or LMWH (enoxaparin), 40 mg, subcutaneously, daily within 24 h postoperatively, for 35 days after HA and 14 days after KA. Crossover was planned once the registration target was met for the first arm.The primary end point is symptomatic VTE within 90 days. Secondary outcomes include readmission, reoperation, major bleeding and death within 90 days, and reoperation and patient-reported pain, function and health status at 6 months.The main analyses will focus on the primary and secondary outcomes for patients undergoing elective primary total HA and KA for osteoarthritis. The analysis will use an intention-to-treat approach with cluster summary methods to compare treatment arms. As the trial stopped early, analyses will account for incomplete cluster crossover and unequal cluster sizes.ConclusionsThis paper provides a detailed statistical analysis plan for CRISTAL.Trial registrationAustralian and New Zealand Clinical Trials Registry ACTRN12618001879257. Registered on 19/11/2018.
Highlights
This a priori statistical analysis plan describes the analysis for CRISTAL
This paper provides a detailed statistical analysis plan for CRISTAL
The only randomised trials have been underpowered or have used an alternative form of prophylaxis (e.g., low molecular weight heparin (LMWH) or a novel oral anticoagulant (NOAC)) for the immediate postoperative period following hip arthroplasty (HA) or knee arthroplasty (KA) prior to changing to aspirin for extended prophylaxis, which does not reflect the way aspirin is used in Australia [12, 13]
Summary
This a priori statistical analysis plan describes the analysis for CRISTAL. Despite the increasing use of aspirin as a sole chemotherapeutic agent for symptomatic venous thromboembolic event (VTE) prophylaxis following hip arthroplasty (HA) and knee arthroplasty (KA) [1], there remains limited highquality comparative evidence for its safety and efficacy. CRISTAL is a pragmatic, multicentre clusterrandomised, two-period cross-sectional crossover trial that aims to determine if aspirin is non-inferior to LMWH in the prevention of symptomatic VTE following HA and KA. It is nested within the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). After an unplanned interim analysis in which the trial stopping rule was met, patient registration was ceased in December 2020, resulting in incomplete crossover. This statistical analysis plan details the planned analyses for CRISTAL to facilitate transparency of data analysis. The trial protocol has previously been published [15]
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