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.

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.

CRISTAL: protocol for 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.

INTRODUCTION: Venous 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 ANALYSIS: This 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 DISSEMINATION: Ethics 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.

The currency, completeness and quality of systematic reviews of acute management of moderate to severe traumatic brain injury: A comprehensive evidence map.

OBJECTIVE: To appraise the currency, completeness and quality of evidence from systematic reviews (SRs) of acute management of moderate to severe traumatic brain injury (TBI). METHODS: We conducted comprehensive searches to March 2016 for published, English-language SRs and RCTs of acute management of moderate to severe TBI. Systematic reviews and RCTs were grouped under 12 broad intervention categories. For each review, we mapped the included and non-included RCTs, noting the reasons why RCTs were omitted. An SR was judged as 'current' when it included the most recently published RCT we found on their topic, and 'complete' when it included every RCT we found that met its inclusion criteria, taking account of when the review was conducted. Quality was assessed using the AMSTAR checklist (trichotomised into low, moderate and high quality). FINDINGS: We included 85 SRs and 213 RCTs examining the effectiveness of treatments for acute management of moderate to severe TBI. The most frequently reviewed interventions were hypothermia (n = 17, 14.2%), hypertonic saline and/or mannitol (n = 9, 7.5%) and surgery (n = 8, 6.7%). Of the 80 single-intervention SRs, approximately half (n = 44, 55%) were judged as current and two-thirds (n = 52, 65.0%) as complete. When considering only the most recently published review on each intervention (n = 25), currency increased to 72.0% (n = 18). Less than half of the 85 SRs were judged as high quality (n = 38, 44.7%), and nearly 20% were low quality (n = 16, 18.8%). Only 16 (20.0%) of the single-intervention reviews (and none of the five multi-intervention reviews) were judged as current, complete and high-quality. These included reviews of red blood cell transfusion, hypothermia, management guided by intracranial pressure, pharmacological agents (various) and prehospital intubation. Over three-quarters (n = 167, 78.4%) of the 213 RCTs were included in one or more SR. Of the remainder, 17 (8.0%) RCTs post-dated or were out of scope of existing SRs, and 29 (13.6%) were on interventions that have not been assessed in SRs. CONCLUSION: A substantial number of SRs in acute management of moderate to severe TBI lack currency, completeness and quality. We have identified both potential evidence gaps and also substantial research waste. Novel review methods, such as Living Systematic Reviews, may ameliorate these shortcomings and enhance utility and reliability of the evidence underpinning clinical care.

Pharmacological interventions in traumatic brain injury: Can we rely on systematic reviews for evidence?

INTRODUCTION: Providing current, reliable and evidence based information for clinicians and researchers in a synthesised and summarised way can be challenging particularly in the area of traumatic brain injury where a vast number of reviews exists. These reviews vary in their methodological quality and are scattered across varying sources. In this paper, we present an overview of systematic reviews that evaluate the pharmacological interventions in traumatic brain injury (TBI). By doing this, we aim to evaluate the existing evidence for improved outcomes in TBI with pharmacological interventions, and to identify gaps in the literature to inform future research. METHODS: We searched the Neurotrauma Evidence Map on systematic reviews relating to pharmacological interventions for managing TBI in acute phase. Two reviewers independently screened search results and appraised each systematic review using the validated AMSTAR tool and extracted data from the review. RESULTS: A total of 288 systematic reviews relating to TBI were available on the Neurotrauma Evidence Map at the time of this study. We identified 19 systematic reviews on pharmacological management for acute TBI with publications dates ranging from 1998 to 2014. The studies were of varying methodological quality, with a mean AMSTAR score of 7.78 (range 2-11]. CONCLUSION: The evidence from high quality systematic reviews show that there is currently insufficient evidence for the use of magnesium, monoaminergic and dopamine agonists, progesterone, aminosteroids, excitatory amino acid inhibitors, haemostatic and antifibrinolytic drugs in TBI. Anti-convulsants are only effective in reducing early seizures with no significant difference between phenytoin and leviteracetam. There is no difference between propofol and midazolam for sedation in TBI patients and ketamine may not cause increased ICP. Overviews of systematic review provide informative and powerful summaries of evidence based research.

Wound management in disaster settings.

BACKGROUND: Few guidelines exist for the initial management of wounds in disaster settings. As wounds sustained are often contaminated, there is a high risk of further complications from infection, both local and systemic. Healthcare workers with little to no surgical training often provide early wound care, and where resources and facilities are also often limited, and clear appropriate guidance is needed for early wound management. METHODS: We undertook a systematic review focusing on the nature of wounds in disaster situations, and the outcomes of wound management in recent disasters. We then presented the findings to an international consensus panel with a view to formulating a guideline for the initial management of wounds by first responders and subsequent healthcare personnel as they deploy. RESULTS: We included 62 studies in the review that described wound care challenges in a diverse range of disasters, and reported high rates of wound infection with multiple causative organisms. The panel defined a guideline in which the emphasis is on not closing wounds primarily but rather directing efforts toward cleaning, debridement, and dressing wounds in preparation for delayed primary closure, or further exploration and management by skilled surgeons. CONCLUSION: Good wound care in disaster settings, as outlined in this article, can be achieved with relatively simple measures, and have important mortality and morbidity benefits.

Postoperative complications and mortality in older patients having non-cardiac surgery at three Melbourne teaching hospitals.

OBJECTIVE: To determine the incidence of postoperative complications, including 30-day mortality rate, and need for intensive care unit (ICU) admission in older patients after non-cardiac surgery. DESIGN AND SETTING: Prospective observational study of all patients aged 70 years or older having elective and non-elective, non-cardiac surgery, and staying at least 1 night after surgery in one of three Melbourne teaching hospitals, June to September 2004. MAIN OUTCOME MEASURES: Postoperative complications and 30-day mortality rate. RESULTS: 1102 consecutive patients were audited in mid 2004; 70% had pre-existing comorbidities. The 30-day mortality rate was 6%; 19% had postoperative complications; and 20% of patients spent at least 1 night in ICU. On multivariate analysis, preoperative factors associated with 30-day mortality included age (odds ratio [OR], 1.09 per year over 70 years; 95% CI, 1.04-1.13; P < 0.001); increasing severity of systemic disease (American Society of Anesthesiologists physical status classification) (OR, 2.53; 95% CI, 1.65-3.86; P < 0.001); and albumin level < 30 g/L (OR, 2.23; 95% CI, 1.09-4.57; P = 0.03). Postoperative factors associated with 30-day mortality were unplanned ICU admission (OR, 3.95; 95% CI, 1.63-9.55; P = 0.003); sepsis (OR, 2.75; 95% CI, 1.17-6.47; P = 0.02); and acute renal impairment (OR, 2.40; 95% CI, 1.06-5.41; P = 0.04). Thoracic surgery was the only surgical specialty significantly associated with mortality (OR, 3.96; 95% CI, 1.44-9.10; P = 0.008) in the multivariate analysis. CONCLUSION: Older patients having surgery had high rates of comorbidities and postoperative complications, placing considerable demands on critical care services. Patient factors were often stronger predictors of mortality than the type of surgery.