Identifying trauma patients with benefit from direct transportation to Level-1 trauma centers

Background Prehospital triage protocols typically try to select patients with Injury Severity Score (ISS) above 15 for direct transportation to a Level-1 trauma center. However, ISS does not necessarily discriminate between patients who benefit from immediate care at Level-1 trauma centers. The aim of this study was to assess which patients benefit from direct transportation to Level-1 trauma centers. Methods We used the American National Trauma Data Bank (NTDB), a retrospective observational cohort. All adult patients (ISS > 3) between 2015 and 2016 were included. Patients who were self-presenting or had isolated limb injury were excluded. We used logistic regression to assess the association of direct transportation to Level-1 trauma centers with in-hospital mortality adjusted for clinically relevant confounders. We used this model to define benefit as predicted probability of mortality associated with transportation to a non-Level-1 trauma center minus predicted probability associated with transportation to a Level-1 trauma center. We used a threshold of 1% as absolute benefit. Potential interaction terms with transportation to Level-1 trauma centers were included in a penalized logistic regression model to study which patients benefit. Results We included 388,845 trauma patients from 232 Level-1 centers and 429 Level-2/3 centers. A small beneficial effect was found for direct transportation to Level-1 trauma centers (adjusted Odds Ratio: 0.96, 95% Confidence Interval: 0.92–0.99) which disappeared when comparing Level-1 and 2 versus Level-3 trauma centers. In the risk approach, predicted benefit ranged between 0 and 1%. When allowing for interactions, 7% of the patients (n = 27,753) had more than 1% absolute benefit from direct transportation to Level-1 trauma centers. These patients had higher AIS Head and Thorax scores, lower GCS and lower SBP. A quarter of the patients with ISS > 15 were predicted to benefit from transportation to Level-1 centers (n = 26,522, 22%). Conclusions Benefit of transportation to a Level-1 trauma centers is quite heterogeneous across patients and the difference between Level-1 and Level-2 trauma centers is small. In particular, patients with head injury and signs of shock may benefit from care in a Level-1 trauma center. Future prehospital triage models should incorporate more complete risk profiles.

Identifying adults with acute rhinosinusitis in primary care that benefit most from antibiotics: protocol of an individual patient data meta-analysis using multivariable risk prediction modelling

IntroductionAcute rhinosinusitis (ARS) is a prime reason for doctor visits and among the conditions with highest antibiotic overprescribing rates in adults. To reduce inappropriate prescribing, we aim to predict the absolute benefit of antibiotic treatment for individual adult patients with ARS by applying multivariable risk prediction methods to individual patient data (IPD) of multiple randomised placebo-controlled trials.Methods and analysisThis is an update and re-analysis of a 2008 IPD meta-analysis on antibiotics for adults with clinically diagnosed ARS. First, the reference list of the 2018 Cochrane review on antibiotics for ARS will be reviewed for relevant studies published since 2008. Next, the systematic searches of CENTRAL, MEDLINE and Embase of the Cochrane review will be updated to 1 September 2020. Methodological quality of eligible studies will be assessed using the Cochrane Risk of Bias 2 tool. The primary outcome is cure at 8–15 days. Regression-based methods will be used to model the risk of being cured based on relevant predictors and treatment, while accounting for clustering. Such model allows for risk predictions as a function of treatment and individual patient characteristics and hence gives insight into individualised absolute benefit. Candidate predictors will be based on literature, clinical reasoning and availability. Calibration and discrimination will be evaluated to assess model performance. Resampling techniques will be used to assess internal validation. In addition, internal–external cross-validation procedures will be used to inform on between-study differences and estimate out-of-sample model performance. Secondarily, we will study possible heterogeneity of treatment effect as a function of outcome risk.Ethics and disseminationIn this study, no identifiable patient data will be used. As such, the Medical Research Involving Humans Subject Act (WMO) does not apply and official ethical approval is not required. Results will be submitted for publication in international peer-reviewed journals.PROSPERO registration numberCRD42020220108.

Breast Cancer Index and prediction of benefit from extended endocrine therapy based on treatment compliance: An IDEAL study.

531 Background: The IDEAL trial randomized hormone receptor-positive (HR+) breast cancer patients to 5 vs 2.5y of extended letrozole after completion of 5y of adjuvant endocrine therapy. In the parent trial, approximately 60% of patients overall were compliant with endocrine treatment (59% vs 74% compliance in 5y and 2.5y arms, respectively), with patient experiences as the most significant factors leading to treatment discontinuation. Breast Cancer Index is a gene expression-based signature that predicts which HR+ patients are likely to benefit from extended endocrine therapy (EET) vs those unlikely to benefit [BCI (H/I)-High and -Low, respectively]. The current study examined EET compliance and outcome by BCI (H/I) status in patients treated in the IDEAL trial. Methods: Patients with available primary tumor specimens were eligible for this blinded study. Primary endpoint was recurrence-free interval (RFI), including locoregional and distant recurrences. Kaplan-Meier and Cox proportional hazards regression analysis were used to analyze the benefit of EET. Non-compliance was defined as completion of ≤60% of treatment duration (≤3y for 5y arm; ≤1.5y for 2.5y arm) for any reason other than disease events. Overtreatment was defined as % compliant BCI (H/I)-Low patients in the 5y arm; undertreatment was % noncompliant BCI (H/I)-High patients in the 5y arm. Results: 908 HR+ patients (73% pN+, 59y, 45% pT1, 48% pT2) were included. 78% (n = 708) of patients were compliant, of which 48% (n = 338) were BCI (H/I)-High and 52% (n = 370) were BCI (H/I)-Low. In non-compliant patients (22%, n = 200), 45% (n = 91) were BCI (H/I)-High and 55% (n = 109) were BCI (H/I)-Low. BCI (H/I)-Low patients irrespective of compliance status did not derive significant benefit from EET (P = 0.922, compliant subset; 0.894 non-compliant subset). Compliant BCI (H/I)-High patients showed significant benefit from EET (HR 0.35, 95% CI 0.16-0.79; absolute benefit 11.7%; P = 0.008) whereas non-compliant BCI (H/I)-High patients did not (HR 0.75, 95% CI 0.17-3.35; absolute benefit 2.1%, P = 0.704). In this study, 38% of patients in the 5y EET arm were BCI (H/I)-Low and compliant and thus were overtreated, while 13% of patients in the 5y EET arm were BCI (H/I)-High and non-compliant and thus were undertreated. Conclusions: Patients that were BCI (H/I)-Low did not derive significant benefit from 5 vs 2.5y of EET even when compliant, and thus may be considered for treatment de-escalation. Importantly, BCI (H/I)-High patients with endocrine responsive disease showed significant improvements in outcome when compliant and should be guided to continue treatment. BCI may serve as an important genomic tool to increase EET compliance and identify patients that may be candidates for increased side effect management and support to potentially improve outcomes. Clinical trial information: NTR3077; BOOG 2006-05; Eudra-CT 2006-003958-16.

Evolution of the Complex Partnerships between Banks and B2B e-Trading Platforms: A Theoretical Interpretation from the Chinese Market

Based on the principal-agent theory, we give a theoretical interpretation on evolution of the complex partnerships between the online SCF (supply chain finance) providers in China. First, we describe the principal-agent relationships and analyze the optimal profit-sharing contracts between the banks and the B2B platforms. Then, from a dual perspective of leadership transfer and absolute benefit change, we explain the behavioral choices of the banks in the cooperation. Results show that, at the initial stage of growth of the platforms’ abilities to rate online borrowers, the leadership and the absolute benefit of the banks will suffer a “double decline,” which explains why the leading banks in China “divorced” the B2B platforms during 2011 to 2013. However, as the platforms’ rating abilities grow to “maturity,” the absolute benefit of the banks will finally exceed its original level, and then the rational banks would cooperate with the platforms again even at the expense of losing a portion of their leadership, which answers why the banks in China have come back to “remarry” the B2B platforms since 2014.

Predicting Expected Absolute Chemotherapy Treatment Benefit in Women With Early-Stage Breast Cancer Using EndoPredict, an Integrated 12-Gene Clinicomolecular Assay

PURPOSE Previous studies have shown EndoPredict (EPclin), a test that integrates 12-gene expression data with nodal status and tumor size, to be predictive for risk of distant recurrence in women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative early-stage breast cancer. Here, we modeled expected absolute chemotherapy benefit on the basis of EPclin test results. METHODS The effect of chemotherapy was modeled using previously validated 10-year risk of distant recurrence as a function of EPclin score for patients treated without chemotherapy. Average relative chemotherapy benefit to reduce breast cancer distant recurrence was evaluated using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group. Absolute chemotherapy benefit differences were estimated across a range of interaction strengths between relative chemotherapy benefit and EPclin score. The average absolute benefit was calculated for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics. RESULTS The average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% in the absence of interaction and 1.5% for maximal interaction. Conversely, the expected average absolute chemotherapy benefit for patients with a high EPclin score was 5.3% and 7.3% for no interaction and maximal interaction, respectively. CONCLUSION For women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative early-stage breast cancer, a high EPclin score identified which patients would benefit most from adjuvant chemotherapy in terms of absolute reduction of distant recurrence, regardless of the amount of interaction between EPclin and relative chemotherapy benefit. A high degree of prognostic discrimination for distant recurrence is more important for identifying patients likely to benefit most from chemotherapy than an interaction between EPclin and treatment-relative benefit.

Development and validation of a novel MR imaging predictor of response to induction chemotherapy in locoregionally advanced nasopharyngeal cancer: a randomized controlled trial substudy (NCT01245959)

Background In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. Methods All patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. Results Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25–0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (pinteraction < 0.001). This trend was also found in the validation cohort with high (n = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06–0.51, p < 0.001) and low ICTOS (n = 175, p = 0.31), with a significant treatment interaction (pinteraction = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors. Conclusion An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment. Trial registration ClinicalTrials.gov, NCT01245959. Registered 23 November 2010.

4114Efficacy of alirocumab treatment after acute coronary syndrome according to new ACC/AHA guidelines for lipid-lowering therapy

Background The 2018 ACC/AHA cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with LDL-C ≥1.8 mmol/L despite maximally tolerated statin therapy who are considered “very high-risk” on the basis of history of multiple ischaemic events or an ischaemic event and multiple high-risk conditions. Purpose We examined the frequency of major adverse cardiovascular events (MACE) and efficacy of PCSK9 inhibition with alirocumab to reduce MACE in patients with recent acute coronary syndrome (ACS) categorized as very high-risk or not very high-risk by guideline criteria. Methods Patients in ODYSSEY OUTCOMES (n=18,924) with recent ACS and residual dyslipidaemia despite optimal statin therapy were randomized to alirocumab or placebo and followed for median 2.8 years. The primary MACE outcome was a composite of coronary heart disease death, non-fatal myocardial infarction (MI), ischaemic stroke, or hospitalization for unstable angina. Results Of 18,924 randomized patients, 11,935 (63.1%) were categorized as very high-risk and 6989 (36.9%) as not very high risk (per ACC/AHA guidelines criteria). In the very high-risk category, 4450 (37.3%) had a prior ischaemic event plus the trial-qualifying index ACS (MI, 3633; stroke, 524; peripheral artery disease, 759); 7485 (62.7%) had no ischaemic event before the index ACS but had ≥2 high-risk conditions (diabetes, 3319; age ≥65 years, 3087; current smoking, 2371; chronic kidney disease, 1583). In the placebo group, the incidence of MACE was higher among those in the very high-risk category (14.4%) vs those not at very high-risk (5.6%). Overall, alirocumab reduced the risk of MACE vs placebo (9.5% vs 11.1%, hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.78–0.93; P=0.003), with consistent relative reductions in both risk categories (very high risk HR 0.84, 95% CI 0.76–0.92; not very high risk HR 0.86, 95% CI 0.70–1.06). However, the absolute reduction in MACE with alirocumab was greater among patients classified as very high-risk (2.1%) vs not very high risk (0.8%), and greater in particular among those classified as very high risk based on multiple ischaemic events (2.4%, Figure). Conclusions Application of 2018 ACC/AHA cholesterol guidelines criteria accurately identifies patients with ACS and dyslipidaemia who are at very high risk for recurrent MACE, and who derive a large absolute benefit from alirocumab treatment. Patients categorized as very high-risk based upon multiple ischaemic events derive a particularly large absolute benefit from treatment with alirocumab. Acknowledgement/Funding Supported by Sanofi and Regeneron Pharmaceuticals