Diagnostic Accuracy of D-Dimer for Acute Aortic Syndromes: Systematic Review and Meta-Analysis.

STUDY OBJECTIVE: Acute aortic syndrome is a life-threatening emergency condition. Previous systematic reviews of D-dimer diagnostic accuracy for acute aortic syndrome have been contradictory and based on limited data, but recently published studies offer potential for a more definitive overview. We aimed to perform a systematic review and meta-analysis to determine the diagnostic accuracy of D-dimer for diagnosing acute aortic syndrome. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic cohort studies (prospective or retrospective) that assessed the use of D-dimer for diagnosing acute aortic syndrome compared with a reference standard test (eg, computed tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two independent reviewers completed study selection, data extractions and quality assessment using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Data were synthesized using a bivariate meta-analysis model. RESULTS: Of 2017 potentially relevant citations, 25 cohort studies met the inclusion criteria, and 18 reporting the 500 ng/mL threshold were included in the primary meta-analysis. Risk of bias domains were mostly unclear due to limited study reporting. The summary sensitivity was 96.5% (95% credible interval [CrI] 94.8% to 98%) and summary specificity was 56.2% (95% CrI, 48.3% to 63.9%). Study specificity varied markedly from 33% to 86%, indicating substantial heterogeneity. Sensitivity analysis including the 7 studies reporting other thresholds showed summary sensitivity of 95.7% (95% CrI, 93.2% to 97.5%) and summary specificity of 57.5% (95% CrI, 50.1% to 64.6%). CONCLUSION: D-dimer concentration has high sensitivity (96.5%) and moderate specificity (56.2%) for acute aortic syndrome, with some uncertainty around estimates due to risk of bias and heterogeneity. Previous meta-analysis reporting higher specificity may be explained by inclusion of case-control studies that may overestimate accuracy.

Diagnostic accuracy of alternative biomarkers for acute aortic syndrome: a systematic review.

BACKGROUND: D-dimer is the only biomarker currently recommended in guidelines for the diagnosis of acute aortic syndrome (AAS). We undertook a systematic review to determine whether any alternative biomarkers could be useful in AAS diagnosis. METHODS: We searched electronic databases (including MEDLINE, EMBASE and the Cochrane Library) from inception to February 2024. Diagnostic studies were eligible if they examined biomarkers other than D-dimer for diagnosing AAS compared with a reference standard test in people presenting to the ED with symptoms of AAS. Case-control studies were identified but excluded due to high risk of bias. Selection of studies, data extraction and risk of bias assessments using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool were undertaken independently by at least two reviewers. We used narrative synthesis to summarise the findings. RESULTS: We identified 2017 citations, included 13 cohort studies (n=76-999), and excluded 38 case-control studies. Methodological quality was variable, with most included studies having unclear or high risk of bias and applicability concerns in at least one item of the QUADAS-2 tool. Only two studies reported biomarkers with sensitivity and specificity comparable to D-dimer (ie, >90% and >50%, respectively). Wang et al reported 99.1% sensitivity and 84.9% specificity for soluble ST2; however, these findings conflicted with estimates of 58% sensitivity and 70.8% specificity reported in another study. Chun and Siu reported 95.6% sensitivity and 56.1% specificity for neutrophil count, but this has not been confirmed elsewhere. CONCLUSION: There are many potential alternative biomarkers for AAS but few have been evaluated in more than one study, study designs are often weak and reported biomarker accuracy is modest or inconsistent between studies. Alternative biomarkers to D-dimer are not ready for routine clinical use. PROSPERO REGISTRATION NUMBER: CRD42022252121.

Thromboprophylaxis in lower limb immobilisation after injury (TiLLI).

Venous thromboembolic disease is a major global cause of morbidity and mortality. An estimated 10 million episodes are diagnosed yearly; over half of these episodes are provoked by hospital admission/procedures and result in significant loss of disability adjusted life years. Temporary lower limb immobilisation after injury is a significant contributor to the overall burden of venous thromboembolism (VTE). Existing evidence suggests that pharmacological prophylaxis could reduce overall VTE event rates in these patients, but the proportional reduction of symptomatic events remains unclear. Recent studies have used different pharmacological agents, dosing regimens and outcome measures. Consequently, there is wide variation in thromboprophylaxis strategies, and international guidelines continue to offer conflicting advice for clinicians. In this review, we provide a summary of recent evidence assessing both the clinical and cost effectiveness of thromboprophylaxis in patients with temporary immobilisation after injury. We also examine the evidence supporting stratified thromboprophylaxis and the validity of widely used risk assessment methods.

GENE EXPRESSION PROFILING AND EXPANDED IMMUNOHISTOCHEMISTRY TESTS TO GUIDE SELECTION OF CHEMOTHERAPY REGIMENS IN BREAST CANCER MANAGEMENT: A SYSTEMATIC REVIEW.

OBJECTIVES: The aim of this report was to assess the clinical effectiveness of two Gene expression profiling (GEP) and two expanded immunohistochemistry (IHC) tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer. METHODS: A systematic review of the evidence on clinical effectiveness of OncotypeDX, IHC4, MammaPrint, and Mammostrat, compared with current clinical practice using clinicopathological parameters, in women with early breast cancer was conducted. Ten databases were searched to include citations to May 2016. RESULTS: Searches identified 7,064 citations, of which forty-one citations satisfied the criteria for the review. A narrative synthesis was performed. Evidence for OncotypeDX demonstrated the impact of the test on decision making and there was some support for OncotypeDX predicting chemotherapy benefit. There were relatively lower levels of evidence for the other three tests included in the analysis. MammaPrint, Mammostrat, and IHC4 tests were limited to a small number of studies. Limitations in relation to study design were identified for all tests. CONCLUSIONS: The evidence base for OncotypeDX is considered to be the most robust. Methodological weaknesses relating to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence were identified. Further evidence is required for all of the tests using prospective randomized controlled trial data.

The use of rapid review methods in health technology assessments: 3 case studies.

BACKGROUND: Rapid reviews are of increasing importance within health technology assessment due to time and resource constraints. There are many rapid review methods available although there is little guidance as to the most suitable methods. We present three case studies employing differing methods to suit the evidence base for each review and outline some issues to consider when selecting an appropriate method. METHODS: Three recently completed systematic review short reports produced for the UK National Institute for Health Research were examined. Different approaches to rapid review methods were used in the three reports which were undertaken to inform the commissioning of services within the NHS and to inform future trial design. We describe the methods used, the reasoning behind the choice of methods and explore the strengths and weaknesses of each method. RESULTS: Rapid review methods were chosen to meet the needs of the review and each review had distinctly different challenges such as heterogeneity in terms of populations, interventions, comparators and outcome measures (PICO) and/or large numbers of relevant trials. All reviews included at least 10 randomised controlled trials (RCTs), each with numerous included outcomes. For the first case study (sexual health interventions), very diverse studies in terms of PICO were included. P-values and summary information only were presented due to substantial heterogeneity between studies and outcomes measured. For the second case study (premature ejaculation treatments), there were over 100 RCTs but also several existing systematic reviews. Data for meta-analyses were extracted directly from existing systematic reviews with new RCT data added where available. For the final case study (cannabis cessation therapies), studies included a wide range of interventions and considerable variation in study populations and outcomes. A brief summary of the key findings for each study was presented and narrative synthesis used to summarise results for each pair of interventions compared. CONCLUSIONS: Rapid review methods need to be chosen to meet both the nature of the evidence base of a review and the challenges presented by the included studies. Appropriate methods should be chosen after an assessment of the evidence base.

Sexual health risk reduction interventions for people with severe mental illness: a systematic review.

BACKGROUND: Despite variability in sexual activity among people with severe mental illness, high-risk sexual behavior (e.g. unprotected intercourse, multiple partners, sex trade and illicit drug use) is common. Sexual health risk reduction interventions (such as educational and behavioral interventions, motivational exercises, counselling and service delivery), developed and implemented for people with severe mental illness, may improve participants' knowledge, attitudes, beliefs behaviors or practices (including assertiveness skills) and could lead to a reduction in risky sexual behavior. This systematic review evaluates the effectiveness of sexual health risk reduction interventions for people with severe mental illness. METHODS: Thirteen electronic databases (including MEDLINE, EMBASE and PsycINFO) were searched to August 2014, and supplemented by hand-searching relevant articles and contacting experts. All controlled trials (randomized or non-randomized) comparing the effectiveness of sexual health risk reduction interventions with usual care for individuals living in the community with severe mental illness were included. Outcomes included a range of biological, behavioral and proxy endpoints. Narrative synthesis was used to combine the evidence. RESULTS: Thirteen controlled trials (all from the USA) were included. Although there was no clear and consistent evidence that interventions reduce the total number of sex partners or improved behavioral intentions in sexual risk behavior, positive effects were generally observed in condom use, condom protected intercourse and on measures of HIV knowledge, attitudes to condom use and sexual behaviors and practices. However, the robustness of these findings is low due to the large between study variability, small sample sizes and low-to-moderate quality of included studies. CONCLUSIONS: There is insufficient evidence at present to fully support or reject the identified sexual health risk reduction interventions for people with severe mental illness. Given the serious consequences of high-risk sexual behaviors, there is an urgent need for well-designed UK based trials, as well as training and support for staff implementing sexual health risk reduction interventions. TRIAL REGISTRATION: PROSPERO CRD42013003674 .

Diagnostic accuracy of the aortic dissection detection risk score alone or with D-dimer for acute aortic syndromes: Systematic review and meta-analysis.

OBJECTIVES: To evaluate the diagnostic accuracy of the aortic dissection detection risk score (ADD-RS) used alone or in combination with D-dimer for detecting acute aortic syndrome (AAS) in patients presenting with symptoms suggestive of AAS. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2024. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched. All diagnostic accuracy studies that assessed the use of ADD-RS alone or with D-Dimer for diagnosing AAS compared with a reference standard test (e.g. computer tomographic angiography (CTA), ECG-gated CTA, echocardiography, magnetic resonance angiography, operation, or autopsy) were included. Two reviewers independently selected and extracted data. Risk of bias was appraised using QUADAS-2 tool. Data were synthesised using hierarchical meta-analysis models. RESULTS: We selected 13 studies from the 2017 citations identified, including six studies evaluating combinations of ADD-RS alongside D-dimer>500ng/L. Summary sensitivities and specificities (95% credible interval) were: ADD-RS>0 94.6% (90%, 97.5%) and 34.7% (20.7%, 51.2%), ADD-RS>1 43.4% (31.2%, 57.1%) and 89.3% (80.4%, 94.8%); ADD RS>0 or D-Dimer>500ng/L 99.8% (98.7%, 100%) and 21.8% (12.1%, 32.6%); ADD RS>1 or D-Dimer>500ng/L 98.3% (94.9%, 99.5%) and 51.4% (38.7%, 64.1%); ADD RS>1 or ADD RS = 1 with D-dimer>500ng/L 93.1% (87.1%, 96.3%) and 67.1% (54.4%, 77.7%). CONCLUSIONS: Combinations of ADD-RS and D-dimer can be used to select patients with suspected AAS for imaging with a range of trade-offs between sensitivity (93.1% to 99.8%) and specificity (21.8% to 67.1%).

Effectiveness and cost effectiveness of pharmacological thromboprophylaxis for medical inpatients: decision analysis modelling study.

Objective: To determine the balance of costs, risks, and benefits for different thromboprophylaxis strategies for medical patients during hospital admission. Design: Decision analysis modelling study. Setting: NHS hospitals in England. Population: Eligible adult medical inpatients, excluding patients in critical care and pregnant women. Interventions: Pharmacological thromboprophylaxis (low molecular weight heparin) for all medical inpatients, thromboprophylaxis for none, and thromboprophylaxis given to higher risk inpatients according to risk assessment models (Padua, Caprini, IMPROVE, Intermountain, Kucher, Geneva, and Rothberg) previously validated in medical cohorts. Main outcome measures: Lifetime costs and quality adjusted life years (QALYs). Costs were assessed from the perspective of the NHS and Personal Social Services in England. Other outcomes assessed were incidence and treatment of venous thromboembolism, major bleeds including intracranial haemorrhage, chronic thromboembolic complications, and overall survival. Results: Offering thromboprophylaxis to all medical inpatients had a high probability (>99%) of being the most cost effective strategy (at a threshold of £20 000 (€23 440; $25 270) per QALY) in the probabilistic sensitivity analysis, when applying performance data from the Padua risk assessment model, which was typical of that observed across several risk assessment models in a medical inpatient cohort. Thromboprophylaxis for all medical inpatients was estimated to result in 0.0552 additional QALYs (95% credible interval 0.0209 to 0.1111) while generating cost savings of £28.44 (-£47 to £105) compared with thromboprophylaxis for none. No other risk assessment model was more cost effective than thromboprophylaxis for all medical inpatients when assessed in deterministic analysis. Risk based thromboprophylaxis was found to have a high (76.6%) probability of being the most cost effective strategy only when assuming a risk assessment model with very high sensitivity is available (sensitivity 99.9% and specificity 23.7% v base case sensitivity 49.3% and specificity 73.0%). Conclusions: Offering pharmacological thromboprophylaxis to all eligible medical inpatients appears to be the most cost effective strategy. To be cost effective, any risk assessment model would need to have a very high sensitivity resulting in widespread thromboprophylaxis in all patients except those at the very lowest risk, who could potentially avoid prophylactic anticoagulation during their hospital stay.

Thromboprophylaxis during pregnancy and the puerperium: a systematic review and economic evaluation to estimate the value of future research.

Background: Pharmacological prophylaxis to prevent venous thromboembolism is currently recommended for women assessed as being at high risk of venous thromboembolism during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide thromboprophylaxis involves weighing the benefits, harms and costs, which vary according to the individual's venous thromboembolism risk. It is unclear whether the United Kingdom's current risk stratification approach could be improved by further research. Objectives: To quantify the current decision uncertainty associated with selecting women who are pregnant or in the puerperium for thromboprophylaxis and to estimate the value of one or more potential future studies that would reduce that uncertainty, while being feasible and acceptable to patients and clinicians. Methods: A decision-analytic model was developed which was informed by a systematic review of risk assessment models to predict venous thromboembolism in women who are pregnant or in the puerperium. Expected value of perfect information analysis was used to determine which factors are associated with high decision uncertainty and should be the target of future research. To find out whether future studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood-thinning drugs and surveyed healthcare professionals. Expected value of sample information analysis was used to estimate the value of potential future research studies. Results: The systematic review included 17 studies, comprising 19 unique externally validated risk assessment models and 1 internally validated model. Estimates of sensitivity and specificity were highly variable ranging from 0% to 100% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns. The decision analysis found that there is substantial decision uncertainty regarding the use of risk assessment models to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was uncertainty around the effectiveness of thromboprophylaxis for preventing venous thromboembolism in women who are pregnant or in the puerperium. We found that a randomised controlled trial of thromboprophylaxis in obese postpartum women is likely to have substantial value and is more likely to be acceptable and feasible than a trial recruiting women who have had a previous venous thromboembolism. In unselected postpartum women and women following caesarean section, the poor performance of risk assessment models meant that offering prophylaxis based on these models had less favourable cost effectiveness with lower decision uncertainty. Limitations: The performance of the risk assessment model for obese postpartum women has not been externally validated. Conclusions: Future research should focus on estimating the efficacy of pharmacological thromboprophylaxis in pregnancy and the puerperium, and clinical trials would be more acceptable in women who have not had a previous venous thromboembolism. Study registration: This study is registered as PROSPERO CRD42020221094. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information.

Women who are pregnant or who have given birth in the previous 6 weeks are at increased risk of developing blood clots that can cause serious illness or death. Small doses of blood thinners given by injection are safe in pregnancy and can reduce the risk of blood clots, but they can slightly increase the risk of bleeding. Healthcare professionals use risk assessment tools to decide if a woman is at high risk of blood clots and should be offered blood thinners. We wanted to find out what research would be useful to help them make better decisions. We reviewed previous research to establish which risk assessment tools are best at predicting who will have a blood clot. We then created a mathematical model to predict what would happen when using different risk assessment tools to decide who should be offered blood thinners, both during pregnancy and after giving birth. We found that there was a lot of uncertainty about which women should be offered blood thinners. This was mainly because there have only been a few small studies comparing blood thinners to no treatment in pregnant women or women who have recently given birth. We estimated the value of future studies comparing blood thinners to no treatment, in groups of women with different risk factors, by predicting what information we would gain and how this would be used to improve decisions about using blood thinners. To find out whether these studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood thinners and surveyed healthcare professionals. We found that a study in obese women who have recently given birth would have substantial value and may be more acceptable than a study in pregnant women with a previous blood clot.