Randomized Controlled Trial

. 2023 Jun 1;6(6):e2317838.

doi: 10.1001/jamanetworkopen.2023.17838.

Effect of Aspirin vs Enoxaparin on 90-Day Mortality in Patients Undergoing Hip or Knee Arthroplasty: A Secondary Analysis of the CRISTAL Cluster Randomized Trial

CRISTAL Study Group; Verinder S Sidhu^{1

2}, Thu-Lan Kelly³, Nicole Pratt³, Stephen E Graves⁴, Rachelle Buchbinder⁵, Sam Adie⁶, Kara Cashman⁷, Ilana N Ackerman⁵, Durga Bastiras⁴, Roger Brighton^{8

9}, Alexander W R Burns¹⁰, Beng Hock Chong^{11

12}, Ornella Clavisi¹³, Maggie Cripps¹³, Mark Dekkers¹⁴, Richard de Steiger¹⁵, Michael Dixon¹⁶, Andrew Ellis^{17

18}, Elizabeth C Griffith⁷, David Hale¹⁹, Amber Hansen^{1

2}, Anthony Harris²⁰, Raphael Hau^{15

21}, Mark Horsley²², Dugal James²³, Omar Khorshid²⁴, Leonard Kuo²⁵, Peter L Lewis^{26

27}, David Lieu²⁸, Michelle Lorimer⁷, Samuel J MacDessi^{6

29}, Peter McCombe³⁰, Catherine McDougall³¹, Jonathan Mulford³², Justine Maree Naylor^{1

2}, Richard S Page³³, John Radovanovic³⁴, Michael Solomon³⁵, Rami Sorial³⁶, Peter Summersell³⁷, Phong Tran³⁸, William L Walter^{17

18

39}, Steve Webb^{40

41}, Chris Wilson^{42

43}, David Wysocki⁴⁴, Ian A Harris^{1

2

45}

Affiliations

¹ School of Clinical Medicine, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
² Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
³ Clinical and Health Sciences, Quality Use of Medicines Pharmacy Research Centre, University of South Australia, Adelaide, South Australia, Australia.
⁴ Australian Orthopaedic Association National Joint Replacement Registry, Adelaide, South Australia, Australia.
⁵ School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁶ School of Clinical Medicine, UNSW Medicine & Health, St George & Sutherland Clinical Campuses, Faculty of Medicine and Health, UNSW Sydney, New South Wales, Australia.
⁷ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
⁸ Orthopaedic Department, Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia.
⁹ Orthopaedic Department, Lakeview Private Hospital, Baulkham Hills, Sydney, New South Wales, Australia.
¹⁰ Orthopaedic Department, Calvary John James Hospital, Deakin, Australian Capital Territory, New South Wales, Australia.
¹¹ Department of Medicine, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹² Department of Hematology, New South Wales Pathology, Kogarah Campus, Sydney, New South Wales, Australia.
¹³ Musculoskeletal Australia, Melbourne, Victoria, Australia.
¹⁴ Orthopaedic Department, Greenslopes Private Hospital, Greenslopes, Queensland, Australia.
¹⁵ Department of Surgery, Epworth Healthcare, University of Melbourne, Melbourne, Victoria, Australia.
¹⁶ Orthopaedic Department, Kareena Private Hospital, Sutherland, New South Wales, Australia.
¹⁷ Orthopaedic Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁸ Sydney Musculoskeletal Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁹ Orthopaedic Department, Hornsby and Kuringai Hospital, Hornsby, New South Wales, Australia.
²⁰ Centre for Health Economics, Monash Business School, Monash University, Melbourne, Victoria, Australia.
²¹ Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia.
²² Orthopaedic Department, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
²³ Bendigo Healthcare Group, Bendigo Hospital, Bendigo, Victoria, Australia.
²⁴ Orthopaedic Department, Fremantle Hospital, Fremantle, Perth, Western Australia, Australia.
²⁵ Orthopaedic Department, Canterbury Hospital, Canterbury, New South Wales, Australia.
²⁶ Calvary Adelaide Hospital, Adelaide, South Australia, Australia.
²⁷ Discipline of Medical Specialties, University of Adelaide, Adelaide, South Australia, Australia.
²⁸ Orthopaedic Department, Fairfield Hospital, Fairfield, New South Wales, Australia.
²⁹ Orthopaedic Department, St George Private Hospital, Kogarah, New South Wales, Australia.
³⁰ Orthopaedic Department, Frankston Hospital, Frankston, Victoria, Australia.
³¹ Orthopaedic Department, The Prince Charles Hospital, Chermside, Queensland, Australia.
³² Orthopaedic Department, Launceston General Hospital, Launceston, Tasmania, Australia.
³³ School of Medicine, St John of God Hospital and Barwon Health, Deakin University, Geelong, Australia.
³⁴ Orthopaedic Department, Mater Hospital, Raymond Terrace, Brisbane, Queensland, Australia.
³⁵ Orthopaedic Department, Prince of Wales Hospital, Randwick, New South Wales, Australia.
³⁶ Orthopaedic Department, Nepean Hospital, Penrith, New South Wales, Australia.
³⁷ Orthopaedic Department, Coffs Harbour Base Hospital, Coffs Harbour, New South Wales, Australia.
³⁸ Orthopaedic Department, Western Health, Melbourne, Victoria, Australia.
³⁹ The Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, New South Wales, Australia.
⁴⁰ Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁴¹ St John of God Health Care, Perth, Western Australia, Australia.
⁴² Orthopaedic Department, Flinders Medical Centre, Bedford Park, South Australia, Australia.
⁴³ Department of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
⁴⁴ Orthopaedic Department, Sir Charles Gardiner Hospital, Perth, Western Australia, Australia.
⁴⁵ Institute of Musculoskeletal Health, School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.

PMID: 37294566
PMCID: PMC10257098
DOI: 10.1001/jamanetworkopen.2023.17838

Randomized Controlled Trial

Effect of Aspirin vs Enoxaparin on 90-Day Mortality in Patients Undergoing Hip or Knee Arthroplasty: A Secondary Analysis of the CRISTAL Cluster Randomized Trial

CRISTAL Study Group et al. JAMA Netw Open. 2023.

. 2023 Jun 1;6(6):e2317838.

doi: 10.1001/jamanetworkopen.2023.17838.

Authors

Affiliations

¹ School of Clinical Medicine, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
² Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
³ Clinical and Health Sciences, Quality Use of Medicines Pharmacy Research Centre, University of South Australia, Adelaide, South Australia, Australia.
⁴ Australian Orthopaedic Association National Joint Replacement Registry, Adelaide, South Australia, Australia.
⁵ School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁶ School of Clinical Medicine, UNSW Medicine & Health, St George & Sutherland Clinical Campuses, Faculty of Medicine and Health, UNSW Sydney, New South Wales, Australia.
⁷ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
⁸ Orthopaedic Department, Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia.
⁹ Orthopaedic Department, Lakeview Private Hospital, Baulkham Hills, Sydney, New South Wales, Australia.
¹⁰ Orthopaedic Department, Calvary John James Hospital, Deakin, Australian Capital Territory, New South Wales, Australia.
¹¹ Department of Medicine, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹² Department of Hematology, New South Wales Pathology, Kogarah Campus, Sydney, New South Wales, Australia.
¹³ Musculoskeletal Australia, Melbourne, Victoria, Australia.
¹⁴ Orthopaedic Department, Greenslopes Private Hospital, Greenslopes, Queensland, Australia.
¹⁵ Department of Surgery, Epworth Healthcare, University of Melbourne, Melbourne, Victoria, Australia.
¹⁶ Orthopaedic Department, Kareena Private Hospital, Sutherland, New South Wales, Australia.
¹⁷ Orthopaedic Department, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁸ Sydney Musculoskeletal Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁹ Orthopaedic Department, Hornsby and Kuringai Hospital, Hornsby, New South Wales, Australia.
²⁰ Centre for Health Economics, Monash Business School, Monash University, Melbourne, Victoria, Australia.
²¹ Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia.
²² Orthopaedic Department, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
²³ Bendigo Healthcare Group, Bendigo Hospital, Bendigo, Victoria, Australia.
²⁴ Orthopaedic Department, Fremantle Hospital, Fremantle, Perth, Western Australia, Australia.
²⁵ Orthopaedic Department, Canterbury Hospital, Canterbury, New South Wales, Australia.
²⁶ Calvary Adelaide Hospital, Adelaide, South Australia, Australia.
²⁷ Discipline of Medical Specialties, University of Adelaide, Adelaide, South Australia, Australia.
²⁸ Orthopaedic Department, Fairfield Hospital, Fairfield, New South Wales, Australia.
²⁹ Orthopaedic Department, St George Private Hospital, Kogarah, New South Wales, Australia.
³⁰ Orthopaedic Department, Frankston Hospital, Frankston, Victoria, Australia.
³¹ Orthopaedic Department, The Prince Charles Hospital, Chermside, Queensland, Australia.
³² Orthopaedic Department, Launceston General Hospital, Launceston, Tasmania, Australia.
³³ School of Medicine, St John of God Hospital and Barwon Health, Deakin University, Geelong, Australia.
³⁴ Orthopaedic Department, Mater Hospital, Raymond Terrace, Brisbane, Queensland, Australia.
³⁵ Orthopaedic Department, Prince of Wales Hospital, Randwick, New South Wales, Australia.
³⁶ Orthopaedic Department, Nepean Hospital, Penrith, New South Wales, Australia.
³⁷ Orthopaedic Department, Coffs Harbour Base Hospital, Coffs Harbour, New South Wales, Australia.
³⁸ Orthopaedic Department, Western Health, Melbourne, Victoria, Australia.
³⁹ The Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local Health District, Sydney, New South Wales, Australia.
⁴⁰ Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁴¹ St John of God Health Care, Perth, Western Australia, Australia.
⁴² Orthopaedic Department, Flinders Medical Centre, Bedford Park, South Australia, Australia.
⁴³ Department of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
⁴⁴ Orthopaedic Department, Sir Charles Gardiner Hospital, Perth, Western Australia, Australia.
⁴⁵ Institute of Musculoskeletal Health, School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.

PMID: 37294566
PMCID: PMC10257098
DOI: 10.1001/jamanetworkopen.2023.17838

Abstract

Importance: Ischemic heart disease remains the leading cause of mortality following hip and knee arthroplasty. Due to its antiplatelet and cardioprotective properties, aspirin has been proposed as an agent that could reduce mortality when used as venous thromboembolism (VTE) prophylaxis following these procedures.

Objective: To compare aspirin with enoxaparin in reducing 90-day mortality for patients undergoing hip or knee arthroplasty procedures.

Design, setting, and participants: This study was a planned secondary analysis of the CRISTAL cluster randomized, crossover, registry-nested trial performed across 31 participating hospitals in Australia between April 20, 2019, and December 18, 2020. The aim of the CRISTAL trial was to determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE following hip or knee arthroplasty. The primary study restricted the analysis to patients undergoing total hip or knee arthroplasty for a diagnosis of osteoarthritis only. This study includes all adult patients (aged ≥18 years) undergoing any hip or knee arthroplasty procedure at participating sites during the course of the trial. Data were analyzed from June 1 to September 6, 2021.

Interventions: Hospitals were randomized to administer all patients oral aspirin (100 mg daily) or subcutaneous enoxaparin (40 mg daily) for 35 days after hip arthroplasty and 14 days after knee arthroplasty procedures.

Main outcomes and measures: The primary outcome was mortality within 90 days. The between-group difference in mortality was estimated using cluster summary methods.

Results: A total of 23 458 patients from 31 hospitals were included, with 14 156 patients allocated to aspirin (median [IQR] age, 69 [62-77] years; 7984 [56.4%] female) and 9302 patients allocated to enoxaparin (median [IQR] age, 70 [62-77] years; 5277 [56.7%] female). The mortality rate within 90 days of surgery was 1.67% in the aspirin group and 1.53% in the enoxaparin group (estimated difference, 0.04%; 95% CI, -0.05%-0.42%). For the subgroup of 21 148 patients with a nonfracture diagnosis, the mortality rate was 0.49% in the aspirin group and 0.41% in the enoxaparin group (estimated difference, 0.05%; 95% CI, -0.67% to 0.76%).

Conclusions and relevance: In this secondary analysis of a cluster randomized trial comparing aspirin with enoxaparin following hip or knee arthroplasty, there was no significant between-group difference in mortality within 90 days when either drug was used for VTE prophylaxis.

Trial registration: http://anzctr.org.au Identifier: ACTRN12618001879257.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Walter reported receiving personal fees from Matortho, Smith&Nephew, Microport, and Johnson & Johnson; grants from Johnson & Johnson; and owning equity in Matortho and Navbit outside the submitted work. No other disclosures were reported.

Figures

**Figure 1.. Site and Patient Enrollment, Randomization, and Follow-up of Participating Hospitals and Patients by Treatment Allocation Group**

**Figure 2.. Kaplan-Meier Analysis of Mortality by Allocation Group**

See this image and copyright information in PMC

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Effect of Aspirin vs Enoxaparin on 90-Day Mortality in Patients Undergoing Hip or Knee Arthroplasty: A Secondary Analysis of the CRISTAL Cluster Randomized Trial

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Effect of Aspirin vs Enoxaparin on 90-Day Mortality in Patients Undergoing Hip or Knee Arthroplasty: A Secondary Analysis of the CRISTAL Cluster Randomized Trial

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