The Clinical Effectiveness of Denosumab (Prolia®) for the Treatment of Osteoporosis in Postmenopausal Women, Compared to Bisphosphonates, Selective Estrogen Receptor Modulators (SERM), and Placebo: A Systematic Review and Network Meta-Analysis.

To assess the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs; bazedoxifene, raloxifene) or placebo, for the treatment of osteoporosis in postmenopausal women (PMW). Systematic searches were run in PubMed, Embase & Cochrane Library on 27-April-2022. Randomized controlled trials (RCTs) that included osteoporotic PMW allocated to denosumab, SERMs, bisphosphonates, or placebo were eligible for inclusion. RCTs were appraised using Cochrane Risk of Bias 2.0. Bayesian network and/or pairwise meta-analyses were conducted on predetermined outcomes (i.e. vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, adverse events [AEs], serious AEs (SAEs), withdrawals due to AEs, AEs caused by denosumab discontinuation). A total of 12 RCTs (k = 22 publications; n = 25,879 participants) were included in the analyses. Denosumab, reported a statistically significant increase in lumbar spine (LS) and total hip (TH) BMD, compared to placebo. Similarly, denosumab also resulted in a statistically significant increase in TH BMD compared to the raloxifene and bazedoxifene. However, relative to denosumab, alendronate, ibandronate and risedronate resulted in significant improvements in both femoral neck (FN) and LS BMD. With regards to vertebral fractures and all safety outcomes, there were no statistically significant differences between denosumab and any of the comparator. Relative to placebo, denosumab was associated with significant benefits in both LS and TH BMD. Additionally, denosumab (compared to placebo) was not associated with reductions in vertebral and nonvertebral fractures. Finally, denosumab was not associated with improvement in safety outcomes, compared to placebo. These findings should be interpreted with caution as some analyses suffered from statistical imprecision.

The clinical effectiveness of denosumab (Prolia®) in patients with hormone-sensitive cancer receiving endocrine therapy, compared to bisphosphonates, selective estrogen receptor modulators (SERM), and placebo: a systematic review and network meta-analysis.

This systematic review (SR) assessed the use of denosumab (Prolia®) to treat osteoporosis in cancer patients receiving endocrine therapy. Denosumab was found to prevent vertebral fractures and improve bone mineral density in cancer patients with osteoporosis. This is the first SR to assess treating osteoporotic cancer patients with denosumab. PURPOSE: This study assessed the effectiveness and safety of denosumab (Prolia®) compared to bisphosphonates (alendronate, ibandronate, risedronate, zoledronate), selective estrogen receptor modulators (SERMs) (bazedoxifene, raloxifene) and placebo for the treatment of osteoporosis in hormone-sensitive cancer patients receiving endocrine therapy (men with prostate cancer [MPC] on hormone ablation therapy [HAT], and women with breast cancer [WBC] on adjuvant aromatase inhibitor therapy [AAIT]). METHODS: Systematic literature searches were conducted in three biomedical databases to identify randomized controlled trials (RCTs). Frequentist network meta-analyses and/or pairwise meta-analyses were performed on predetermined outcomes (i.e., vertebral/nonvertebral fractures, bone mineral density [BMD], mortality, treatment-related adverse events [AEs], serious AEs [SAEs], withdrawal due to treatment-related AEs). RESULTS: A total of 14 RCTs (15 publications) were included. Denosumab was found to prevent vertebral fractures in cancer patients receiving endocrine therapy, relative to placebo. Similarly, denosumab, zoledronate, and alendronate improved BMD at the femoral neck (FN) and lumbar spine (LS) in MPC on HAT, relative to placebo. Denosumab, ibandronate and risedronate improved BMD at the LS and total hip (TH) in WBC on AAIT, relative to placebo. Denosumab and risedronate improved trochanteric (TRO) BMD in WBC on AAIT, relative to placebo. Similarly, denosumab improved FN BMD in WBC on AAIT. CONCLUSION: In MPC on HAT, denosumab (relative to placebo) was effective at preventing vertebral fractures and improving BMD at the FN and LS. Moreover, in WBC on AAIT, denosumab (relative to placebo) improved BMD at the FN, LS, TH, and TRO, as well as prevent vertebral fracture.

In-hospital survival after pancreatoduodenectomy is greater in high-volume hospitals versus lower-volume hospitals: a meta-analysis.

BACKGROUND: Variation in cut-off values for what is considered a high volume (HV) hospital has made assessments of volume-outcome relationships for pancreaticoduodenectomy (PD) challenging. Accordingly, we performed a systematic review and meta-analysis comparing in-hospital mortality after PD in hospitals above and below HV thresholds of various cut-off values. METHOD: PubMed/MEDLINE, Embase and Cochrane Library were searched to 4 January 2021 for studies comparing in-hospital mortality after PD in hospitals above and below defined HV thresholds. After data extraction, risk of bias was assessed using the Downs and Black checklist. A random-effects model was used for meta-analysis, including meta-regressions. Registration: PROSPERO, CRD42021224432. RESULTS: From 1855 records, 17 observational studies of moderate quality were included. Median HV cut-off was 25 PDs/year (IQR: 20-32). Overall relative risk of in-hospital mortality was 0.37 (95% CI: 0.30, 0.45), that is, 63% less in HV hospitals. All subgroup analyses found an in-hospital survival benefit in performing PDs at HV hospitals. Meta-regressions from included studies found no statistically significant associations between relative risk of in-hospital mortality and region (USA vs. non-USA; p = 0.396); or 25th percentile (p = 0.231), median (p = 0.822) or 75th percentile (p = 0.469) HV cut-off values. Significant inverse relationships were found between PD hospital volume and other outcomes. CONCLUSION: In-hospital survival was significantly greater for patients undergoing PDs at HV hospitals, regardless of HV cut-off value or region. Future research is required to investigate regions where low-volume centres have specialized PD infrastructure and the potential impact on mortality.

Safety and effectiveness of aspirin and enoxaparin for venous thromboembolism prophylaxis after total hip and knee arthroplasty: a systematic review.

BACKGROUND: Patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) are at risk of venous thromboembolism (VTE). Australian orthopaedic guidelines recommend aspirin and low-molecular-weight heparin (e.g. enoxaparin) for VTE prophylaxis; however, there is debate in the international literature around the use of aspirin as VTE prophylaxis. This review assesses the risks and benefits of aspirin compared to enoxaparin as VTE prophylaxis for patients undergoing THA or TKA. METHODS: A systematic review was conducted to identify relevant randomized controlled trials. Studies comparing enoxaparin, aspirin and/or placebo for VTE prophylaxis in THA or TKA patients were included. Network meta-analysis (NMA) was performed to calculate risk ratios (RRs) and confidence intervals (CIs). Quality appraisal was conducted by assessing risk of bias and the strength of the evidence. RESULTS: Nine randomized controlled trials were eligible for inclusion. The NMA found no statistically significant differences for the investigated outcomes: total DVT rates (RR = 1.21, 95% CI 0.86, 1.72), symptomatic pulmonary embolism (PE) rates (RR = 1.02, 95% CI 0.02, 50.86), major haemorrhage (RR = 0.97, 95% CI 0.02, 50.99) and wound complication (RR = 0.73, 95% CI 0.17, 3.20). The occurrence of PE was rare. Due to limited data, sub-group analysis was not possible. The overall quality of evidence in the NMA is considered to be very low. CONCLUSION: This review did not find statistically significant differences between aspirin and enoxaparin. Future studies should identify more evidence, particularly for rare outcomes such as PE, as this might help decision-makers to get consensus on the use of aspirin as VTE prophylaxis.

Morbidity and mortality meetings: gold, silver or bronze?

BACKGROUND: Morbidity and mortality (M&M) meetings contribute to surgical education and improvements in patient care through the review of surgical outcomes; however, they often lack defined structure, objectives and resource support. The aim of this study was to investigate the factors that impact the effective conduct of M&M meetings. METHODS: We conducted a rapid systematic literature review. Three biomedical databases (PubMed, the Cochrane Library and the University of York Centre for Reviews and Dissemination), clinical practice guideline clearinghouses and grey literature sources were searched from May 2009 to September 2016. Studies that evaluated the function of a hospital-based M&M process were included. Two independent reviewers conducted study selection and data extraction. Study details and key findings were reported narratively. RESULTS: Nineteen studies identified enablers, and seven identified barriers, to the effective conduct of M&M meetings. Enabling factors for effective M&M meetings included a structured meeting format, a structured case identification and presentation, and a systems focus. Absence of key personnel from meetings, lack of education regarding the meeting process, poor perceptions of the process, logistical issues and heterogeneity in case evaluation were identified as barriers to effective M&M meetings. CONCLUSION: Taking steps to standardize and incorporate the enabling factors into M&M meetings will ensure that the valuable time spent reviewing M&M is used effectively to improve patient care.

Gadoxetic acid-enhanced MRI for the characterization of hepatocellular carcinoma: A systematic review and meta-analysis.

PURPOSE: To establish the relative diagnostic accuracy of gadoxetic acid-enhanced magnetic resonance imaging (GA-MRI) compared with contrast-enhanced computed tomography (CE-CT), dynamic MRI (D-MRI), gadopentetic acid-enhanced MRI (GP-MRI), or gadobenic acid-enhanced MRI (GB-MRI) in the characterization of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: PubMed, EMBASE, the Cochrane Library, and the University of York CRD databases were searched to February 29 2016 for any studies that compared the diagnostic accuracy of GA-MRI to CE-CT, D-MRI, GP-MRI, or GB-MRI in patients with known or suspected HCC. Diagnostic accuracy outcomes (true positive, true negative, false positive, false negative) were extracted and analyzed using the bivariate model of Reitsma et al (2005). RESULTS: In studies comparing GA-MRI to CE-CT in patients with any-sized lesions, estimated sensitivities were 0.881 (95% confidence interval [CI] = 0.766, 0.944) and 0.713 (95% CI = 0.577, 0.819) respectively. Estimated specificities were 0.926 (95% CI = 0.829, 0.97) and 0.918 (95% CI = 0.829, 0.963), respectively. This difference was not statistically significant. In studies including patients with small lesions GA-MRI was superior to CE-CT, with estimated sensitivities of 0.919 (95% CI = 0.834, 0.962) and 0.637 (95% CI = 0.565, 0.704 and estimated specificities of 0.936 (95% CI = 0.882, 0.966) and 0.971 (95% CI = 0.937, 0.987), respectively. In studies comparing GA-MRI to D-MRI in patients with any-sized lesions estimated sensitivities were 0.907 (95% CI = 0.870, 0.934) and 0.820 (95% CI = 0.776, 0.857); estimated specificities were 0.929 (95% CI = 0.877, 0.961) and 0.934 (95% CI = 0.881, 0.964). CONCLUSION: GA-MRI has superior diagnostic ability to CE-CT in patients with small lesions. In patients with any-sized lesions there is no evidence that GA-MRI is superior to either CE-CT to D-MRI. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:281-290.

Practical applications of rapid review methods in the development of Australian health policy.

Rapid reviews (RRs) are a method of evidence synthesis that can provide robust evidence to support policy decisions in a timely manner. Herein we describe the methods used to conduct RRs and present an illustrative case study to describe how RRs can be used to inform contemporary Australian health policy. The aim of the present study was to explore several important aspects of how RRs can inform decision makers. RRs are conducted within limited time frames of as little as 4 weeks. Policy questions may focus on issues of efficacy, service delivery and service organisation rather than reimbursement of new services, which is better answered by a more comprehensive assessment. RRs use flexible and pragmatic methods, which aim to balance the objectivity and rigour required of the reviews within limited time frames. This flexibility allows for great variation across products with regard to length, depth of analysis and methods used. As a result, RRs can be specifically tailored to address targeted policy questions and are a useful tool in the development of Australian health policy.

Public health advocacy in action: the case of unproven breast cancer screening in Australia.

In recent years, nonmammographic breast imaging devices, such as thermography, electrical impedance scanning and elastography, have been promoted directly to consumers, which has captured the attention of governments, researchers and health organisations. These devices are not supported by evidence and risk undermining existing mammographic breast cancer screening services. During a 5-year period, Cancer Council Western Australia (CCWA) used strategic research combined with legal, policy and media advocacy to contest claims that these devices were proven alternatives to mammography for breast cancer screening. The campaign was successful because it had input from people with public health, academic, clinical and legal backgrounds, and took advantage of existing legal and regulatory avenues. CCWA's experience provides a useful advocacy model for public health practitioners who are concerned about unsafe consumer products, unproven medical devices, and misleading health information and advertising.

Comparative diagnostic accuracy of hepatocyte-specific gadoxetic acid (Gd-EOB-DTPA) enhanced MR imaging and contrast enhanced CT for the detection of liver metastases: a systematic review and meta-analysis.

PURPOSE: This systematic review evaluated the diagnostic accuracy and impact on patient management of hepatocyte-specific gadoxetic acid enhanced magnetic resonance imaging (GA-MRI) compared to contrast enhanced computed tomography (CE-CT) in patients with liver metastases. METHOD: Four biomedical databases (PubMed, EMBASE, Cochrane Library, York CRD) were searched from January 1991 to February 2016. Studies investigating the accuracy or management impact of GA-MRI compared to CE-CT in patients with known or suspected liver metastases were included. Bias was evaluated using QUADAS-II. Univariate meta-analysis of sensitivity ratios (RR) were conducted in the absence of heterogeneity, calculated using I 2 , Tau values (τ) and prediction intervals. RESULTS: Nine diagnostic accuracy studies (537 patients with 1216 lesions) and four change in management studies (488 patients with 281 lesions) were included. Per-lesion sensitivity and specificity estimates for GA-MRI ranged from 86.9-100.0 % and 80.2-98.0 %, respectively, compared to 51.8-84.6 % and 77.2-98.0 % for CE-CT. Meta-analysis found GA-MRI to be significantly more sensitive than CE-CT (RR = 1.29, 95 % CI = 1.18-1.40, P < 0.001), with equivalent specificity (RR = 0.97, 95 % CI 0.910-1.042, P = 0.44). The largest difference was observed for lesions smaller than 10 mm for which GA-MRI was significantly more sensitive (RR = 2.21, 95 % CI = 1.47-3.32, P < 0.001) but less specific (RR = 0.92, 95 % CI 0.87-0.98, P = 0.008). GA-MRI affected clinical management in 26 of 155 patients (16.8 %) who had a prior CE-CT; however, no studies investigated the consequences of using GA-MRI instead of CE-CT. CONCLUSION: GA-MRI is significantly more sensitive than CE-CT for detecting liver metastases, which leads to a modest impact on patient management in the context of an equivocal CE-CT result.

Stereotactic anatomical localization in complex sinus surgery: A systematic review and meta-analysis.

OBJECTIVE: It is recognized that stereotactic anatomical localization (SAL) is a useful tool in endoscopic sinus surgery (ESS), but it may be most beneficial for complex rather than routine sinus procedures. This review sought to determine the safety and efficacy of SAL in complex indications for ESS. DATA SOURCES: PubMed, EMBASE, Centre for Reviews and Dissemination, and the Cochrane Library were searched from inception up to April 4, 2014. REVIEW METHODS: English studies comparing ESS with and without SAL in complex cases were included. Complex surgery included revision surgery, inverted papilloma, extensive sinus disease, or biopsy of tumors that are not exophytic. Safety outcomes included total, major, minor, orbital, dural, and major hemorrhage complications. Efficacy outcomes included operation completion, revision surgery, and patient-reported outcomes. Meta-analysis generated fixed-effects Mantel-Haenszel odds ratios (OR) and confidence intervals (CI). RESULTS: A total of 2,381 studies were identified, of which nine met the inclusion criteria. Meta-analyses indicated a reduction in the likelihood of total (OR = 0.58; 95% CI, 0.37-0.92), major (OR = 0.36; 95% CI, 0.18-0.75), and orbital complications (OR = 0.38; 95% CI, 0.17-0.83). There was no demonstrated benefit of SAL at reducing revision surgery (OR = 0.64; 95% CI, 0.38-1.08), major hemorrhage (OR = 0.77; 95% CI, 0.29-2.06), or minor complications (OR = 0.85; 95% CI, 0.48-1.50). CONCLUSION: Due to the rare outcomes under investigation, the included primary studies largely lacked the power to identify a statistically meaningful effect of SAL in ESS. However, meta-analyses of primary studies demonstrated a decreased likelihood of total, major, and orbital complications in complex ESS with the use of SAL.

Content analysis of Australian direct-to-consumer websites for emerging breast cancer imaging devices.

OBJECTIVE: To describe the nature and frequency of information presented on direct-to-consumer websites for emerging breast cancer imaging devices. DESIGN: Content analysis of Australian website advertisements from 2 March 2011 to 30 March 2012, for three emerging breast cancer imaging devices: digital infrared thermal imaging, electrical impedance scanning and electronic palpation imaging. MAIN OUTCOME MEASURES: Type of imaging offered, device safety, device performance, application of device, target population, supporting evidence and comparator tests. RESULTS: Thirty-nine unique Australian websites promoting a direct-to-consumer breast imaging device were identified. Despite a lack of supporting evidence, 22 websites advertised devices for diagnosis, 20 advertised devices for screening, 13 advertised devices for prevention and 13 advertised devices for identifying breast cancer risk factors. Similarly, advertised ranges of diagnostic sensitivity (78%-99%) and specificity (44%-91%) were relatively high compared with published literature. Direct comparisons with conventional screening tools that favoured the new device were highly prominent (31 websites), and one-third of websites (12) explicitly promoted their device as a suitable alternative. CONCLUSIONS: Australian websites for emerging breast imaging devices, which are also available internationally, promote the use of such devices as safe and effective solutions for breast cancer screening and diagnosis in a range of target populations. Many of these claims are not supported by peer-reviewed evidence, raising questions about the manner in which these devices and their advertising material are regulated, particularly when they are promoted as direct alternatives to established screening interventions.

A systematic review of elastography, electrical impedance scanning, and digital infrared thermography for breast cancer screening and diagnosis.

The objective of this study aimed to systematically identify and evaluate all the available evidence of safety, effectiveness and diagnostic accuracy for three emerging classes of technology promoted for breast cancer screening and diagnosis: Digital infrared thermal imaging (DITI), electrical impedance scanning (EIS) and elastography. A systematic search of seven biomedical databases (EMBASE, PubMed, Web of Science, CRD, CINAHL, Cochrane Library, Current Contents Connect) was conducted through March 2011, along with a manual search of reference lists from relevant studies. The principal outcome measures were safety, effectiveness, and diagnostic accuracy. Data were extracted using a standardised form, and validated for accuracy by the secondary authors. Study quality was appraised using the quality assessment of diagnostic accuracy studies tool, while heterogeneity was assessed using forest plots, Cooks' distance and standardised residual scatter plots, and I (2) statistics. From 6,808 search results, 267 full-text articles were assessed, of which 60 satisfied the inclusion criteria. No effectiveness studies were identified. Only one EIS screening accuracy study was identified, while all other studies involved symptomatic populations. Significant heterogeneity was present among all device classes, limiting the potential for meta-analyses. Sensitivity and specificity varied greatly for DITI (Sens 0.25-0.97, Spec 0.12-0.85), EIS (Sens 0.26-0.98, Spec 0.08-0.81) and ultrasound elastography (Sens 0.35-1.00, Spec 0.21-0.99). It is concluded that there is currently insufficient evidence to recommend the use of these technologies for breast cancer screening. Moreover, the high level of heterogeneity among studies of symptomatic women limits inferences that may be drawn regarding their use as diagnostic tools. Future research employing standardised imaging, research and reporting methods is required.