Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty
Authors:   CRISTAL Study Group, Sidhu Verinder S. , Kelly Thu-Lan , Pratt Nicole , Graves Stephen E. , Buchbinder Rachelle , Adie Sam , Cashman Kara , Ackerman Ilana , Bastiras Durga , Brighton Roger , Burns Alexander W. R. , Chong Beng Hock , Clavisi Ornella , Cripps Maggie , Dekkers Mark , de Steiger Richard , Dixon Michael , Ellis Andrew , Griffith Elizabeth C. , Hale David , Hansen Amber , Harris Anthony , Hau Raphael , Horsley Mark , James Dugal , Khorshid Omar , Kuo Leonard , Lewis Peter , Lieu David , Lorimer Michelle , MacDessi Samuel , McCombe Peter , McDougall Catherine , Mulford Jonathan , Naylor Justine Maree , Page Richard S. , Radovanovic John , Solomon Michael , Sorial Rami , Summersell Peter , Tran Phong , Walter William L. , Webb Steve , Wilson Chris , Wysocki David , Harris Ian A. 
Published: August 2022

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