Abstract
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.
IntroductionVenous 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 analysisThis 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 disseminationEthics 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.
Owing to its association with prosthetic joint infection, persistent wound drainage has become an important clinical entity after THA or TKA. The association between venous thromboembolism (VTE) ...prophylaxis and persistent wound drainage has not been extensively reported before but has potentially important clinical implications.
(1) Is the type of VTE prophylaxis (enoxaparin or aspirin) used after hip arthroplasty or knee arthroplasty associated with a higher risk of persistent wound drainage? (2) In patients who experience persistent wound drainage, is the type of VTE prophylaxis associated with a longer time taken to achieve a dry wound? (3) Is type of VTE prophylaxis associated with a higher risk of joint-related reoperation within 6 months?
This was a secondary analysis of data from an earlier cluster-randomized trial conducted through the Australian Orthopaedic Association National Joint Replacement Registry; data were drawn from two participating hospitals from that study. According to the trial's allocation sequence, the two participating hospitals were randomized to administer aspirin (100 mg daily) or enoxaparin (40 mg daily) as VTE prophylaxis to all patients undergoing hip arthroplasty for 35 days after the procedure and for all patients undergoing knee arthroplasty for 14 days afterwards. Crossover to the alternate prophylaxis group occurred after the patient enrollment target had been met for the first arm. Between April 2019 and December 2020, 1339 of 1679 eligible patients were included in this study; 82% (707 of 861) of eligible patients were allocated to the enoxaparin group and 77% (632 of 818) of eligible patients we allocated to the aspirin group. The mean age in both groups was 67 ± 10 years and the mean BMI was 32 ± 7 kg/m 2 . There was a higher proportion of male patients (43% 302 of 707 versus 36% 227 of 632; p = 0.01), hip arthroplasties (36% 254 of 707 versus 29% 182 of 632; p = 0.006), and patients receiving subcuticular closure (62% 441 of 707 versus 33% 208 of 631; p < 0.001) in the enoxaparin group than in the aspirin group. Patients were monitored for wound drainage on each postoperative day until discharge, and this was recorded in the medical record once per day. Assessors were not blinded to the type of prophylaxis each patient received. Persistent wound drainage was defined as any wound drainage beyond Postoperative Day 3. For patients who experienced persistent wound drainage, the time taken to achieve a dry wound was defined as the number of days beyond Postoperative Day 3 for the wound to become dry. Logistic regression was used to determine whether the prophylaxis type was associated with persistent wound drainage. For patients with persistent wound drainage, the median time of drainage was compared between groups using the Kruskal-Wallis test. The number of patients undergoing a joint-related reoperation within 6 months was identified through data linkage to the Australian Orthopaedic Association National Joint Replacement Registry and electronic record review, and was compared using a Fisher exact test.
We found no difference between the enoxaparin and aspirin groups in terms of the percentage of patients who had persistent wound drainage (9% 65 of 707 versus 8% 49 of 632, odds ratio 1.2 95% confidence interval 0.8 to 1.8; p = 0.40). For patients receiving subcuticular closure, after controlling for other potentially confounding variables, including age, sex, BMI, preoperative anticoagulant use, and type of arthroplasty, enoxaparin was associated with a higher risk of persistent wound drainage than aspirin (OR 3.6 95% CI 1.5 to 10.6; p = 0.009). For patients receiving a skin staple closure, after controlling for the same variables above, we found enoxaparin was not associated with a higher risk of persistent wound drainage (OR 1.1 95% CI 0.7 to 1.9; p = 0.66). For patients who experienced persistent wound drainage patients (114: 65 in the enoxaparin group and 49 in the aspirin group), there was no difference in the median (interquartile range) time taken to achieve a dry wound (enoxaparin: 1 day IQR 1 to 2 days, aspirin: 1 day IQR 1 to 3 days; p = 0.22). There was no difference in the risk of joint-related reoperation within 6 months between enoxaparin (2.4% 17 of 707) and aspirin (2.2% 14 of 632, OR 1.1 95% CI 0.5 to 2.4; p = 0.86).
Enoxaparin was not associated with an increased risk of persistent wound drainage compared with aspirin for all patients included in this study. Enoxaparin may be associated with a higher risk of drainage for patients receiving subcuticular closure. However, this finding should be interpreted cautiously, given the small sample size in this analysis. The duration of drainage was short regardless of the prophylaxis used, and enoxaparin was not associated with an increased risk of joint-related reoperation. These findings should not deter clinicians from using enoxaparin for VTE prophylaxis after hip or knee arthroplasty.
Level III, therapeutic study.
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