CRISTAL (a 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): statistical analysis plan

Verinder Singh Sidhu; Thu-Lan Kelly; Nicole Pratt; Steven Graves; Rachelle Buchbinder; Justine Naylor; Richard de Steiger; Ilana Ackerman; Sam Adie; Michelle Lorimer; Durga Bastiras; Kara Cashman; Ian Harris

doi:10.1186/s13063-021-05486-0

CRISTAL (a 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): statistical analysis plan

Trials. 2021 Aug 24;22(1):564. doi: 10.1186/s13063-021-05486-0.

Authors

Verinder Singh Sidhu¹, Thu-Lan Kelly², Nicole Pratt², Steven Graves³, Rachelle Buchbinder^{4

5}, Justine Naylor⁶, Richard de Steiger⁷, Ilana Ackerman⁴, Sam Adie⁸, Michelle Lorimer⁹, Durga Bastiras³, Kara Cashman⁹, Ian Harris^{6

10}

Affiliations

¹ Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, South West Sydney Clinical School, The University of New South Wales Sydney, Sydney, NSW, Australia. Verinder.s.sidhu@gmail.com.
² Clinical and Health Sciences, Quality Use of Medicines Pharmacy Research Centre, University of South Australia, Adelaide, Australia.
³ Australian Orthopaedic Association National Joint Replacement Registry, Adelaide, South Australia, Australia.
⁴ Department of Epidemiology and Preventive Medicine, School of Public Health & Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁵ Monash Department of Clinical Epidemiology, Cabrini Institute, Melbourne, Victoria, Australia.
⁶ Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, South West Sydney Clinical School, The University of New South Wales Sydney, Sydney, NSW, Australia.
⁷ Department of Surgery, Epworth Healthcare, University of Melbourne, Melbourne, Victoria, Australia.
⁸ St. George and Sutherland Clinical School, The University of New South Wales Sydney, Sydney, NSW, Australia.
⁹ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
¹⁰ Institute of Musculoskeletal Health, School of Public Health, The University of Sydney, Sydney, NSW, Australia.

Abstract

Background: This a priori statistical analysis plan describes the analysis for CRISTAL.

Methods: CRISTAL (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.

Conclusions: This paper provides a detailed statistical analysis plan for CRISTAL.

Trial registration: Australian and New Zealand Clinical Trials Registry ACTRN12618001879257 . Registered on 19/11/2018.

Keywords: Aspirin; Hip arthroplasty; Knee arthroplasty; Low molecular weight heparin; Statistical analysis plan; Venous thromboembolism.

Publication types

Randomized Controlled Trial

MeSH terms

Adult
Arthroplasty, Replacement, Knee* / adverse effects
Aspirin / adverse effects
Australia
Heparin, Low-Molecular-Weight / adverse effects
Humans
Registries
Venous Thromboembolism* / diagnosis
Venous Thromboembolism* / etiology
Venous Thromboembolism* / prevention & control

Substances

Heparin, Low-Molecular-Weight
Aspirin

Grants and funding

1152285/Department of Health, Australian Government