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.

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.

Post-discharge patient-reported non-adherence to aspirin compared to enoxaparin for venous thromboembolism prophylaxis after hip or knee arthroplasty.

BACKGROUND: Aspirin and enoxaparin are commonly used for venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee arthroplasty (TKA). The purpose of this study was to compare non-adherence after discharge to aspirin or enoxaparin following THA or TKA. METHODS: A subset of participants in the CRISTAL study were selected for participation. Additional inclusion criteria were no preoperative anticoagulant use and discharge from hospital before the prophylaxis period ended. The first four consecutive patients from each arm at each participating hospital were planned to be recruited (planned sample size n = 248). A patient-reported adherence questionnaire was completed by telephone at 36-41 days after THA and at 15-20 days after TKA. The primary outcome was non-adherence. Secondary outcomes were number of missed doses and the reasons for non-adherence. RESULTS: There were 178 participants included from 15 sites, less than planned explained by early stopping of trial recruitment. There was no significant between-group difference in patient-reported non-adherence: 24% (17/71) for aspirin, 30% (32/107) for enoxaparin, odds ratio = 1.4 (95% CI 0.7-2.9). The mean number of missed doses was 2.5 for aspirin and 3.4 for enoxaparin (mean difference = 0.9 doses, 95% CI -1.2 to 3.1). For aspirin, the most commonly reported reason for non-adherence was forgotten doses and for enoxaparin it was clinician-recommended change. CONCLUSIONS: Rates of non-adherence and the number of missing doses were similar for patients regardless of drug prescribed. The most common reasons for non-adherence were unrelated to the mode of administration.

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

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.

Robotic-assisted surgery and kinematic alignment in total knee arthroplasty (RASKAL study): a protocol of a national registry-nested, multicentre, 2×2 factorial randomised trial assessing clinical, intraoperative, functional, radiographic and survivorship outcomes.

INTRODUCTION: Robot-assisted surgery (RAS) and kinematic alignment (KA) are being increasingly adopted to improve patient outcomes in total knee arthroplasty (TKA). There is uncertainty around the individual or combined effect of these concepts compared with computer-assisted surgery (CAS) and mechanical alignment (MA), respectively. This study aims to assess the effectiveness of RAS, KA or both to improve clinical outcomes, functional measures, radiographic precision and prosthetic survivorship when compared with current gold standards of surgical care. METHODS AND ANALYSIS: A national registry-nested, multicentre, double-blinded, 2×2 factorial, randomised trial will be undertaken with 300 patients undergoing primary unilateral TKA performed by 15 surgeons. The primary outcome will be the between-group differences in postoperative change over 2 years in the mean Knee injury and Osteoarthritis Outcome Score (KOOS-12), comparing first, RAS to CAS as its control, and second, KA to MA as its control. Secondary outcomes will include other knee-specific and general health patient-reported outcome measures (PROMs), intraoperative pressure loads as a measure of soft tissue balance, 6-month postoperative functional outcomes, radiological precision using CT imaging, complications and long-term prosthetic survivorship. The contribution of each patient's unique coronal plane alignment of the knee phenotype to primary and secondary PROMs will be investigated. OMERACT-OARSI criteria and Patient Acceptable Symptom State outcome score thresholds for the KOOS-12 and Oxford Knee Score will be used in secondary analyses. Primary intention-to-treat and secondary per-protocol analyses will be performed. Statistical analysis will include a generalised linear mixed model for repeated measures for continuous KOOS-12 scores. Kaplan-Meier estimates with adjusted HRs of implant survivorship will be calculated. ETHICS AND DISSEMINATION: Ethics approval was obtained from Sydney Local Health District-Royal Prince Alfred Hospital (Approval X20-0494 and 2020/ETH02896 10.24/DEC20). Results will be submitted for publication in a peer-reviewed journal and presented in national, state and international meetings. TRIAL REGISTRATION NUMBER: ACTRN12621000205831.

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.

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.