CRISTAL: protocol for 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

Verinder Singh Sidhu; Steven E Graves; Rachelle Buchbinder; Justine Maree Naylor; Nicole L Pratt; Richard S de Steiger; Beng H Chong; Ilana N Ackerman; Sam Adie; Anthony Harris; Amber Hansen; Maggie Cripps; Michelle Lorimer; Steve Webb; Ornella Clavisi; Elizabeth C Griffith; Durga Anandan; Grace O'Donohue; Thu-Lan Kelly; Ian A Harris

doi:10.1136/bmjopen-2019-031657

CRISTAL: protocol for 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

BMJ Open. 2019 Nov 6;9(11):e031657. doi: 10.1136/bmjopen-2019-031657.

Authors

Verinder Singh Sidhu¹, Steven E Graves², Rachelle Buchbinder^{3

4}, Justine Maree Naylor⁵, Nicole L Pratt⁶, Richard S de Steiger⁷, Beng H Chong⁸, Ilana N Ackerman³, Sam Adie⁹, Anthony Harris¹⁰, Amber Hansen⁵, Maggie Cripps⁵, Michelle Lorimer¹¹, Steve Webb^{12

13}, Ornella Clavisi¹⁴, Elizabeth C Griffith¹¹, Durga Anandan², Grace O'Donohue², Thu-Lan Kelly⁶, Ian A Harris^{5

15}

Affiliations

¹ CRISTAL Study Group, Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, University of New South Wales South Western Sydney Clinical School, Liverpool, New South Wales, Australia verinder.s.sidhu@gmail.com.
² Australian Orthopaedic Association National Joint Replacement Registry, Adelaide, South Australia, Australia.
³ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁴ Monash Department of Clinical Epidemiology, Cabrini Institute, Melbourne, Victoria, Australia.
⁵ CRISTAL Study Group, Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, University of New South Wales South Western Sydney Clinical School, Liverpool, New South Wales, Australia.
⁶ School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
⁷ Department of Surgery, Epworth Healthcare, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Department of Haematology, Saint George and Sutherland Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
⁹ Faculty of Medicine, Saint George and Sutherland Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
¹⁰ Monash University Centre for Health Economics, Caufield, Victoria, Australia.
¹¹ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
¹² Department of Intensive Care, St John of God Hospital, Subiaco, Western Australia, Australia.
¹³ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Austria.
¹⁴ Musculoskeletal Australia, Melbourne, Victoria, Australia.
¹⁵ Institute for Musculoskeletal Health, The University of Sydney School of Public Health, Sydney, New South Wales, Australia.

Abstract

Introduction: Venous thromboembolism (VTE) is a serious complication following hip arthroplasty (HA) and knee arthroplasty (KA). This study aims to determine whether aspirin is non-inferior to low molecular weight heparin (LMWH) in preventing symptomatic VTE following HA and KA.

Methods and analysis: This is a cluster randomised, crossover, non-inferiority, trial nested within the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). The clusters will consist of Australian hospitals performing at least 250 HA and/or KA procedures per annum. All adult patients undergoing HA or KA will be included. The intervention will be aspirin, orally, 85-150 mg daily. The comparator will be LMWH (enoxaparin) 40 mg, subcutaneously, daily. Both drugs will commence within 24 hours postoperatively and continue for 35 days after HA and 14 days after KA. Each hospital will be randomised to commence with aspirin or LMWH and then crossover to the alternative treatment after meeting the recruitment target. Data will be collected through the AOANJRR via patient-reported surveys. The primary outcome is symptomatic VTE within 90 days post surgery, verified by AOANJRR staff. The primary analysis will include only patients undergoing elective primary total hip arthroplasty and total knee arthroplasty for osteoarthritis. Secondary outcomes will include symptomatic VTE for all HA and KA (including partial and revision) within 90 days, readmission, reoperation, major bleeding and death within 90 days and reoperation, death and patient-reported pain, function and health status at 6 months. If aspirin is found to be inferior, a cost-effectiveness analysis will be conducted. The study will aim to recruit 15 562 patients from 31 hospitals.

Ethics and dissemination: Ethics approval has been granted. Trial results will be submitted for publication. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618001879257, pre-results) and is endorsed by the Australia and New Zealand Musculoskeletal Clinical Trials Network.

Keywords: aspirin; deep venous thrombosis; hip arthroplasty; knee arthroplasty; low molecular weight heparin; venous thromboembolism.

Publication types

Clinical Trial Protocol
Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Arthroplasty, Replacement, Hip*
Arthroplasty, Replacement, Knee*
Aspirin / therapeutic use*
Australia
Cross-Over Studies
Equivalence Trials as Topic
Fibrinolytic Agents / therapeutic use*
Heparin, Low-Molecular-Weight / therapeutic use*
Humans
Postoperative Complications / prevention & control*
Randomized Controlled Trials as Topic / methods*
Registries
Venous Thromboembolism / prevention & control*

Substances

Fibrinolytic Agents
Heparin, Low-Molecular-Weight
Aspirin

Associated data

ANZCTR/ACTRN12618001879257