Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial

CRISTAL Study Group; Verinder S Sidhu; Thu-Lan Kelly; Nicole Pratt; Stephen E Graves; Rachelle Buchbinder; Sam Adie; Kara Cashman; Ilana Ackerman; Durga Bastiras; Roger Brighton; Alexander W R Burns; Beng Hock Chong; Ornella Clavisi; Maggie Cripps; Mark Dekkers; Richard de Steiger; Michael Dixon; Andrew Ellis; Elizabeth C Griffith; David Hale; Amber Hansen; Anthony Harris; Raphael Hau; Mark Horsley; Dugal James; Omar Khorshid; Leonard Kuo; Peter Lewis; David Lieu; Michelle Lorimer; Samuel MacDessi; Peter McCombe; Catherine McDougall; Jonathan Mulford; Justine Maree Naylor; Richard S Page; John Radovanovic; Michael Solomon; Rami Sorial; Peter Summersell; Phong Tran; William L Walter; Steve Webb; Chris Wilson; David Wysocki; Ian A Harris

doi:10.1001/jama.2022.13416

Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial

JAMA. 2022 Aug 23;328(8):719-727. doi: 10.1001/jama.2022.13416.

Authors

CRISTAL Study Group; Verinder S Sidhu^{1

2}, Thu-Lan Kelly³, Nicole Pratt³, Stephen E Graves⁴, Rachelle Buchbinder^{5

6}, Sam Adie⁷, Kara Cashman⁸, Ilana Ackerman^{5

6}, Durga Bastiras⁴, Roger Brighton^{9

10}, Alexander W R Burns¹¹, Beng Hock Chong^{12

13}, Ornella Clavisi¹⁴, Maggie Cripps^{1

2}, Mark Dekkers¹⁵, Richard de Steiger¹⁶, Michael Dixon¹⁷, Andrew Ellis^{18

19}, Elizabeth C Griffith⁸, David Hale²⁰, Amber Hansen^{1

2}, Anthony Harris²¹, Raphael Hau^{16

22}, Mark Horsley²³, Dugal James²⁴, Omar Khorshid²⁵, Leonard Kuo²⁶, Peter Lewis²⁷, David Lieu²⁸, Michelle Lorimer⁸, Samuel MacDessi^{7

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^{18

19

39}, Steve Webb⁵, Chris Wilson^{40

41}, David Wysocki⁴², Ian A Harris^{1

2

43}

Affiliations

¹ School of Clinical Medicine, UNSW 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 Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁶ Monash-Cabrini Department of Musculoskeletal Health and Clinical Epidemiology, Cabrini Health, Melbourne, Victoria, Australia.
⁷ School of Clinical Medicine, UNSW Medicine and Health, St George and Sutherland Clinical Campuses, Faculty of Medicine and Health, UNSW Sydney, New South Wales, Australia.
⁸ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
⁹ Orthopaedic Department, Westmead Private Hospital, Westmead, Sydney, New South Wales, Australia.
¹⁰ Orthopaedic Department, Lakeview Private Hospital, Baulkham Hills, Sydney, New South Wales, Australia.
¹¹ Orthopaedic Department, Calvary John James Hospital, Deakin, Canberra, Australian Capital Territory, Australia.
¹² Department of Medicine, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹³ Department of Hematology, New South Wales Pathology, Kogarah Campus, Sydney, New South Wales, Australia.
¹⁴ Musculoskeletal Australia, Melbourne, Victoria, Australia.
¹⁵ Orthopaedic Department, Greenslopes Private Hospital, Greenslopes, Brisbane, Queensland, Australia.
¹⁶ Department of Surgery, Epworth Healthcare, University of Melbourne, Melbourne, Victoria, Australia.
¹⁷ Orthopaedic Department, Kareena Private Hospital, Sutherland, Sydney, New South Wales, Australia.
¹⁸ Orthopaedic Department, Royal North Shore Hospital, St Leonard's, Sydney, New South Wales, Australia.
¹⁹ Sydney Musculoskeletal Health Flagship Centre of the University of Sydney and Royal North Shore Hospital, St Leonard's, Sydney, New South Wales, Australia.
²⁰ Orthopaedic Department, Hornsby and Kuringai Hospital, Hornsby, Sydney, New South Wales, Australia.
²¹ Centre for Health Economics, Monash Business School, Monash University, Melbourne, Victoria, Australia.
²² Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia.
²³ Orthopaedic Department, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia.
²⁴ Bendigo Healthcare Group, Bendigo Hospital, Bendigo, Victoria, Australia.
²⁵ Orthopaedic Department, Fremantle Hospital, Fremantle, Western Australia, Australia.
²⁶ Orthopaedic Department, Canterbury Hospital, Canterbury, Sydney, New South Wales, Australia.
²⁷ Orthopaedic Department, Calvary Hospital, Adelaide, South Australia, Australia.
²⁸ Orthopaedic Department, Fairfield Hospital, Fairfield, Sydney, New South Wales, Australia.
²⁹ Orthopaedic Department, St George Private Hospital, Kogarah, Sydney, New South Wales, Australia.
³⁰ Orthopaedic Department, Frankston Hospital, Frankston, Melbourne, Victoria, Australia.
³¹ Orthopaedic Department, The Prince Charles Hospital, Chermside, Brisbane, 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, Victoria, Australia.
³⁴ Orthopaedic Department, Mater Hospital, Raymond Terrace, Brisbane, Queensland, Australia.
³⁵ Orthopaedic Department, Prince of Wales Hospital, Randwick, Sydney, New South Wales, Australia.
³⁶ Orthopaedic Department, Nepean Hospital, Nepean, Sydney, 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 Orthopaedic Department, Flinders Medical Centre, Bedford Park, Adelaide, South Australia, Australia.
⁴¹ Department of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
⁴² Orthopaedic Department, Sir Charles Gardiner Hospital, Perth, Western Australia, Australia.
⁴³ Institute of Musculoskeletal Health, School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.

Abstract

Importance: There remains a lack of randomized trials investigating aspirin monotherapy for symptomatic venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee arthroplasty (TKA).

Objective: To determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE after THA or TKA.

Design, setting, and participants: Cluster-randomized, crossover, registry-nested trial across 31 hospitals in Australia. Clusters were hospitals performing greater than 250 THA or TKA procedures annually. Patients (aged ≥18 years) undergoing hip or knee arthroplasty procedures were enrolled at each hospital. Patients receiving preoperative anticoagulation or who had a medical contraindication to either study drug were excluded. A total of 9711 eligible patients were enrolled (5675 in the aspirin group and 4036 in the enoxaparin group) between April 20, 2019, and December 18, 2020. Final follow-up occurred on August 14, 2021.

Interventions: Hospitals were randomized to administer aspirin (100 mg/d) or enoxaparin (40 mg/d) for 35 days after THA and for 14 days after TKA. Crossover occurred after the patient enrollment target had been met for the first group. All 31 hospitals were initially randomized and 16 crossed over prior to trial cessation.

Main outcomes and measures: The primary outcome was symptomatic VTE within 90 days, including pulmonary embolism and deep venous thrombosis (DVT) (above or below the knee). The noninferiority margin was 1%. Six secondary outcomes are reported, including death and major bleeding within 90 days. Analyses were performed by randomization group.

Results: Enrollment was stopped after an interim analysis determined the stopping rule was met, with 9711 patients (median age, 68 years; 56.8% female) of the prespecified 15 562 enrolled (62%). Of these, 9203 (95%) completed the trial. Within 90 days of surgery, symptomatic VTE occurred in 256 patients, including pulmonary embolism (79 cases), above-knee DVT (18 cases), and below-knee DVT (174 cases). The symptomatic VTE rate in the aspirin group was 3.45% and in the enoxaparin group was 1.82% (estimated difference, 1.97%; 95% CI, 0.54%-3.41%). This failed to meet the criterion for noninferiority for aspirin and was significantly superior for enoxaparin (P = .007). Of 6 secondary outcomes, none were significantly better in the enoxaparin group compared with the aspirin group.

Conclusions and relevance: Among patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE within 90 days, defined as below- or above-knee DVT or pulmonary embolism. These findings may be informed by a cost-effectiveness analysis.

Trial registration: ANZCTR Identifier: ACTRN12618001879257.

Publication types

Comparative Study
Multicenter Study
Randomized Controlled Trial

MeSH terms

Aged
Anticoagulants* / adverse effects
Anticoagulants* / therapeutic use
Arthroplasty, Replacement, Hip* / adverse effects
Arthroplasty, Replacement, Knee* / adverse effects
Aspirin* / adverse effects
Aspirin* / therapeutic use
Australia
Chemoprevention
Enoxaparin* / adverse effects
Enoxaparin* / therapeutic use
Female
Humans
Male
Osteoarthritis / surgery
Postoperative Complications / prevention & control
Pulmonary Embolism / etiology
Pulmonary Embolism / prevention & control
Venous Thromboembolism* / etiology
Venous Thromboembolism* / prevention & control

Substances

Anticoagulants
Enoxaparin
Aspirin