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Objective To determine the effectiveness of nirmatrelvir/ritonavir and molnupiravir among vaccinated and unvaccinated non-hospitalized adults with COVID-19. Methods Observational studies of nirmatrelvir/ritonavir or molnupiravir compared to no antiviral drug treatment for COVID-19 in non-hospitalized adults with data on vaccination status were included. We searched MEDLINE, EMBASE, Scopus, Web of Science, WHO COVID-19 Research Database and medRxiv for reports published between 1 January 2022 and 8 November 2023. The primary outcome was a composite of hospitalization or mortality up to 35 days after COVID-19 diagnosis. Risk of bias was assessed with ROBINS-I. Risk ratios (RR), hazard ratios (HR) and risk differences (RD) were separately estimated using random-effects models. Results We included 30 cohort studies on adults treated with nirmatrelvir/ritonavir (n  = 462 279) and molnupiravir (n  = 48 008). Nirmatrelvir/ritonavir probably reduced the composite outcome (RR 0.62, 95%CI 0.55–0.70; I 2 = 0%; moderate certainty) with no evidence of effect modification by vaccination status (RR P subgroup = 0.47). In five studies, RD estimates against the composite outcome for nirmatrelvir/ritonavir were 1.21% (95%CI 0.57% to 1.84%) in vaccinated and 1.72% (95%CI 0.59% to 2.85%) in unvaccinated subgroups. Molnupiravir may slightly reduce the composite outcome (RR 0.75, 95%CI 0.67–0.85; I 2 = 32%; low certainty). Evidence of effect modification by vaccination status was inconsistent among studies reporting different effect measures (RR P subgroup = 0.78; HR P subgroup = 0.08). In two studies, RD against the composite outcome for molnupiravir were −0.01% (95%CI −1.13% to 1.10%) in vaccinated and 1.73% (95%CI −2.08% to 5.53%) in unvaccinated subgroups. Conclusions Among cohort studies of non-hospitalized adults with COVID-19, nirmatrelvir/ritonavir is effective against the composite outcome of severe COVID-19 independent of vaccination status. Further research and a reassessment of molnupiravir use among vaccinated adults are warranted. Registration PROSPERO CRD42023429232. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the impact of incorporating neoadjuvant chemotherapy (NAC) into the 'quadrifecta' outcomes composite for reporting outcomes of radical cystectomy (RC) creating a pentafecta score. Patients and Methods: This is a retrospective multicentre analysis of patients treated with RC, with or without NAC, for bladder cancer between 2002 and 2023. The primary outcome was the effect of adding NAC to a quadrifecta outcomes composite on cancer‐specific (CSS) and overall survival (OS). The quadrifecta outcomes composite included a yield of ≥16 lymph nodes, negative soft tissue surgical margin, absence of major complication within 30 days from surgery, and no delay in RC. Results: A total of 590 patients were included in the analyses. A total of 233 (39.5%) patients achieved all quadrifecta outcomes and 82 (13.9%) patients were additionally treated with NAC, achieving the pentafecta. Achieving the quadrifecta outcomes composite was significantly associated with better CSS (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.32–0.75; P = 0.001) and OS (HR 0.48, 95% CI 0.34–0.69; P < 0.01). The addition of NAC to the quadrifecta composite outcomes significantly improved the discrimination of patients more likely to have better CSS (HR 0.21, 95% CI 0.08–0.57; P = 0.002) and OS (HR 0.26, 95% CI 0.12–0.55; P < 0.01). Conclusion: We propose a new pentafecta that may serve as a tool for standardising outcomes reporting and measuring the quality of RC. [ABSTRACT FROM AUTHOR]

Introduction The harmful effects of first and secondhand smoking are well-established. Smoke-free laws aim at protecting nonsmokers. This study aimed to assess the impact of the 2013 total ban on indoor smoking in Chile on hospitalizations and deaths of major cardiovascular events. Aims and Methods The logarithm of the monthly hospitalization and death rates, standardized by age for every 100 000 inhabitants, were estimated for ischemic heart disease, acute myocardial infarction, strokes, and a composite outcome of ischemic heart diseases (which includes acute myocardial infarction) and strokes. In addition, interrupted time series with synthetic control groups were used to assess changes in levels and trends after the intervention. Results The total ban on indoor smoking caused significant reductions in death rates for the three diseases studied for age groups above 20 years old. In addition, there were substantial decreases in the post-intervention hospitalization rates for ischemic heart disease: for the 20–44 age group, the decrease was 8.7% compared to the pre-intervention period (p  < .01). In comparison, such a reduction was 4% (p  < .01) for the ≥65 age group. For acute myocardial infarction, the decrease was 11.5% (p  < .01) for the 20–44 age group, while for stroke, it was a 1.2% (p  < .01) decrease for the total population. It is estimated that the smoking ban averted 15.6% of the deaths compared with the synthetic control groups. Conclusions The implementation of total smoke-free environments in Chile contributed to the reduction of mortality for main cardiovascular diseases. This study provides additional evidence of causality linking the policy to health outcomes. Implications The total indoor smoking ban significantly affected age-standardized hospitalization and deaths. The number of deaths averted by this policy is estimated at approximately 4758 and 5256 for IHD and stroke, respectively, during the 2013–2017 period (15.6% fewer deaths than predicted by the synthetic control groups). The study contributes to the body of evidence that supports total indoor smoking bans. [ABSTRACT FROM AUTHOR]

OBJECTIVES Mechanical composite valve grafts (MCVGs) are the first-line therapy for aortic root replacement in young adults. Decellularized aortic homografts (DAH) present a promising novel alternative due to their lower thrombogenicity. We aimed to compare both treatment options regarding survival and valve-related adverse events. METHODS This study was designed as a single-centre retrospective cohort study including patients who underwent root replacement with MCVG or DAH between 2000 and 2022. Urgent or emergent procedures were excluded. RESULTS The study cohort included 289 patients (MCVG n  = 216, DAH n  = 73) with a mean age of 48.5 ± 12 years (MCVG 49 ± 12 years vs DAH 47 ± 11 years; P  = 0.23) and a median EuroScore II of 1.7% (1.2, 2.6). The 30-day mortality was 1% (n  = 3). Cumulative survival at 3 years was 99% for DAH and 94% for MCVG, respectively (P  = 0.15). Mean follow-up was 98.9 ± 72.7 months. Bleeding events (n  = 14, 6.5%) and thromboembolism (n  = 14, 6.5%) were only observed in the MCVG group (P  = 0.19 and 0.09, respectively). Four cases (5%) of moderate structural valve deterioration occurred, all in the DAH group (P  ≤ 0.001). The cumulative incidence of a composite end point of valve-related adverse events was significantly higher in the MCVG group (P  = 0.0295). CONCLUSIONS Aortic root replacement with MCVGs and decellularized aortic homografts showed low mortality in an elective setting. Patients in the homograft cohort demonstrated significantly higher freedom from valve-related adverse events. DAH present a promising treatment option for young patients requiring root replacement; however, data on long-term durability are needed. [ABSTRACT FROM AUTHOR]

Background Type 2 diabetes mellitus (T2DM) is increasingly being diagnosed in older adults. Our objective is to assess the advantages and potential drawbacks of different glucose-lowering medications in this specific population. Methods A network meta-analysis was conducted to identify randomized controlled trials that examined patient-centered outcomes in adults aged ≥65 years with T2DM. We searched PubMed, Cochrane CENTRAL, and Embase up to September 23, 2023. Quality of eligible studies were assessed using the Cochrane RoB 2.0 tool. Results A total of 22 trials that involved 41 654 participants were included, incorporating sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, sulfonylureas (SU) and acarbose. Our findings reveal that GLP-1RAs reduce the risk of major adverse cardiovascular events (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.71 to 0.97) and body weight (mean difference [MD], −3.87 kg; 95% CI, −5.54 to −2.21). SGLT2 inhibitors prevent hospitalization for heart failure (RR, 0.66; 95% CI, 0.57 to 0.77), renal composite outcome (RR, 0.69; 95% CI, 0.53 to 0.89), and reduce body weights (MD, −1.85 kg; 95% CI, −2.42 to −1.27). SU treatment increases the risk of any hypoglycaemia (RR, 4.19; 95% CI, 3.52 to 4.99) and severe hypoglycaemia (RR, 7.06; 95% CI, 3.03 to 16.43). GLP-1RAs, SGLT2 inhibitors, metformin, SU and DPP-4 inhibitors are effective in reducing glycaemic parameters. Notably, the number of treatments needed decreases in most cases as age increases. Conclusions Novel glucose-lowering medications with benefits that outweigh risks should be prioritized for older patients with diabetes. [ABSTRACT FROM AUTHOR]

Background A small proportion of Escherichia coli and Klebsiella pneumoniae demonstrate in vitro non-susceptibility to piperacillin/tazobactam but retain susceptibility to ceftriaxone. Uncertainty remains regarding how best to treat these isolates. Objectives We sought to compare clinical outcomes between patients with piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae bloodstream infection receiving definitive therapy with ceftriaxone versus an alternative effective antibiotic. Methods We retrospectively identified patients with a positive blood culture for piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae between 1 January 2013 and 31 December 2022. Patients were divided into one of two definitive treatment groups: ceftriaxone or alternative effective antibiotic. Our primary outcome was a composite of 90 day all-cause mortality, hospital readmission, or recurrence of infection. We used Cox proportional hazards models to compare time with the composite outcome between groups. Results Sixty-two patients were included in our analysis. Overall, median age was 63 years (IQR 49.5–71.0), the most common source of infection was intra-abdominal (25/62; 40.3%) and the median total duration of therapy was 12.0 days (IQR 9.0–16.8). A total of 9/22 (40.9%) patients in the ceftriaxone treatment group and 18/40 (45.0%) patients in the alternative effective antibiotic group met the composite endpoint. In an adjusted time-to-event analysis, there was no difference in the composite endpoint between groups (HR 0.67, 95% CI 0.30–1.50). The adjusted Bayesian posterior probability that the HR was less than or equal to 1 (i.e. ceftriaxone is as good or better than alternative therapy) was 85%. Conclusions These findings suggest that ceftriaxone can be used to effectively treat bloodstream infections with E. coli or K. pneumoniae that are non-susceptible to piperacillin/tazobactam but susceptible to ceftriaxone. [ABSTRACT FROM AUTHOR]

OBJECTIVES To assess if warfarin targeted to international normalized ratio (INR) 1.8 (range 1.5–2.0) is safe for all patients with an On-X aortic mechanical valve. METHODS This prospective, observational registry follows patients receiving warfarin targeted at an INR of 1.8 (range 1.5–2.0) plus daily aspirin (75–100 mg) after On-X aortic valve replacement. The primary end point is a composite of thromboembolism, valve thrombosis and major bleeding. Secondary end points include the individual rates of thromboembolism, valve thrombosis and major bleeding, as well as the composite in subgroups of home or clinic-monitored INR and risk categorization for thromboembolism. The control was the patient group randomized to standard-dose warfarin (INR 2.0–3.0) plus daily aspirin 81 mg from the PROACT trial. RESULTS A total of 510 patients were enroled at 23 centres in the UK, USA and Canada. Currently, the median follow-up duration is 3.4 years, and median achieved INR is 1.9. The primary composite end point rate in the low INR patients is 2.31% vs 5.39% (95% confidence interval 4.12–6.93%) per patient-year in the PROACT control group, constituting a 57% reduction. Results are consistent in subgroups of home or clinic-monitored, and high-risk patients, with reductions of 56%, 57% and 57%, respectively. Major and total bleeding are decreased by 85% and 73%, respectively, with similar rates of thromboembolic events. No valve thrombosis occurred. CONCLUSIONS Interim results suggest that warfarin targeted at an INR of 1.8 (range 1.5–2.0) plus aspirin is safe and effective in patients with an On-X aortic mechanical valve with or without home INR monitoring. [ABSTRACT FROM AUTHOR]

Abstract Background Optimal medical therapy (OMT) for uncomplicated type B aortic dissection (uTBAD) provides excellent short-term outcomes during follow up; however, its long-term therapeutic effectiveness is unsatisfactory. This study evaluated the predictive value of systemic immune-inflammation index (SII) for adverse events among patients with acute uTBAD undergoing OMT. Methods We performed a retrospective analysis of a prospectively maintained database between 2013 and 2020. The primary end point in this study was composite outcomes including aortic intervention, all-cause mortality, retrograde type A aortic dissection (rTAAD) and aortic diameter growth > 5 mm. The patients were divided into high and low SII groups according to the optimal cut-off value of SII as determined using the receiver operating characteristic curve. Cox proportional hazards models were constructed to estimate the hazards ratios and identify the predictors of composite outcomes. Results A total of 124 patients with acute uTBAD who underwent OMT were enrolled. One patient died during hospitalisation. At the end of a mean follow-up duration of 51 ± 23 months, 53 (43.1%) patients experienced composite outcomes, 15 patients (12.2%) died, 31 (25.2%) underwent aortic intervention, 21 (17.1%) exhibited diameter growth of > 5 mm, and 2 developed rTAAD. The patients were divided into low SII group (n = 78, 62.9%) and high SII group (n = 46, 37.1%) as per the optimal cut-off SII value of 1449. The incidence of composite outcomes in high SII group was significantly higher than that in low SII (28 [60.9%] vs. 26[33.3%], p 1449 at the time of diagnosis is an independent predictor of OMT failure.

Background The Atrial fibrillation Better Care (ABC) pathway is the gold-standard approach to atrial fibrillation (AF) management, but the effect of implementation on health outcomes in care home residents is unknown. Objective To examine associations between ABC pathway adherence and stroke, transient ischaemic attack, cardiovascular hospitalisation, major bleeding, mortality and a composite of all these outcomes in care home residents. Methods A retrospective cohort study of older care home residents (≥65 years) in Wales with AF was conducted between 1 January 2003 and 31 December 2018 using the Secure Anonymised Information Linkage Databank. Adherence to the ABC pathway was assessed at care home entry using pre-specified definitions. Cox proportional hazard and competing risk models were used to estimate the risk of health outcomes according to ABC adherence. Results From 14,493 residents (median [interquartile range] age 87.0 [82.6–91.2] years, 35.2% male) with AF, 5,531 (38.2%) were ABC pathway adherent. Pathway adherence was not significantly associated with risk of the composite outcome (adjusted hazard ratio, 95% confidence interval [CI]: 1.01 [0.97–1.05]). There was a significant independent association observed between ABC pathway adherence and a reduced risk of myocardial infarction (0.70 [0.50–0.98]), but a higher risk of haemorrhagic stroke (1.59 [1.06–2.39]). ABC pathway adherence was not significantly associated with any other individual health outcomes examined. Conclusion An ABC adherent approach in care home residents was not consistently associated with improved health outcomes. Findings should be interpreted with caution owing to difficulties in defining pathway adherence using routinely collected data and an individualised approach is recommended. [ABSTRACT FROM AUTHOR]

Background Phenotypic classification is a method of grouping patients with similar phenotypes. Aim We aimed to use phenotype classification based on a clustering process for risk stratification of patients with non-valvular atrial fibrillation (AF) and second, to assess the benefit of the Atrial Fibrillation Better Care (ABC) pathway. Methods Patients with AF were prospectively enrolled from 27 hospitals in Thailand from 2014 to 2017, and followed up every 6 months for 3 years. Cluster analysis was performed from 46 variables using the hierarchical clustering using the Ward minimum variance method. Outcomes were a composite of all-cause death, ischemic stroke/systemic embolism, acute myocardial infarction and heart failure. Results A total of 3405 patients were enrolled (mean age 67.8 ± 11.3 years, 58.2% male). During the mean follow-up of 31.8 ± 8.7 months. Three clusters were identified: Cluster 1 had the highest risk followed by Cluster 3 and Cluster 2 with a hazard ratio (HR) and 95% confidence interval (CI) of composite outcomes of 2.78 (2.25, 3.43), P  < 0.001 for Cluster 1 and 1.99 (1.63, 2.42), P  < 0.001 for Cluster 3 compared with Cluster 2. Management according to the ABC pathway was associated with reductions in adverse clinical outcomes especially those who belonged to Clusters 1 and 3 with HR and 95%CI of the composite outcome of 0.54 (0.40, 073), P  < 0.001 for Cluster 1 and 0.49 (0.38, 0.63), P  < 0.001 for Cluster 3. Conclusion Phenotypic classification helps in risk stratification and prognostication. Compliance with the ABC pathway was associated with improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Optimal medical therapy (OMT) for uncomplicated type B aortic dissection (uTBAD) provides excellent short-term outcomes during follow up; however, its long-term therapeutic effectiveness is unsatisfactory. This study evaluated the predictive value of systemic immune-inflammation index (SII) for adverse events among patients with acute uTBAD undergoing OMT. Methods: We performed a retrospective analysis of a prospectively maintained database between 2013 and 2020. The primary end point in this study was composite outcomes including aortic intervention, all-cause mortality, retrograde type A aortic dissection (rTAAD) and aortic diameter growth > 5 mm. The patients were divided into high and low SII groups according to the optimal cut-off value of SII as determined using the receiver operating characteristic curve. Cox proportional hazards models were constructed to estimate the hazards ratios and identify the predictors of composite outcomes. Results: A total of 124 patients with acute uTBAD who underwent OMT were enrolled. One patient died during hospitalisation. At the end of a mean follow-up duration of 51 ± 23 months, 53 (43.1%) patients experienced composite outcomes, 15 patients (12.2%) died, 31 (25.2%) underwent aortic intervention, 21 (17.1%) exhibited diameter growth of > 5 mm, and 2 developed rTAAD. The patients were divided into low SII group (n = 78, 62.9%) and high SII group (n = 46, 37.1%) as per the optimal cut-off SII value of 1449. The incidence of composite outcomes in high SII group was significantly higher than that in low SII (28 [60.9%] vs. 26[33.3%], p < 0.01). Patients with high SII demonstrated significantly higher mortality rate than those with a low SII (11 [23.9%] vs. 5 [6.4%], respectively; p < 0.01). In addition, the high SII group had significantly higher rate of aortic-related reinterventions than the low SII group (16 [34.8%] vs. 15 [19.2%], p = 0.03). Multivariable Cox analyses showed that a high SII score was independently associated with composite outcomes rate (hazard ratio, 2.15; 95% confidence interval, 1.22–3.78; p < 0.01). Conclusions: The long-term therapeutic effectiveness of OMT alone in patients with acute uTBAD is unsatisfactory. An SII > 1449 at the time of diagnosis is an independent predictor of OMT failure. [ABSTRACT FROM AUTHOR]

The win ratio is a statistical method most commonly used for analyzing composite outcomes in clinical trials. Composite outcomes comprise two or more distinct "component" events (for example, myocardial infarction or death) and are typically analyzed using time-to-first-event methods ignoring the relative importance of the component events. When using the win ratio, component events are instead placed into a hierarchy from most to least important; more important components can then be prioritized over less important outcomes (for example, death can be prioritized over myocardial infarction). Furthermore, the win ratio enables outcomes of different types (for example, time-to-event, continuous, binary, ordinal, and repeat events) to be combined. We present winratiotest, a command to implement the win-ratio approach for hierarchical outcomes in a flexible and user-friendly way. [ABSTRACT FROM AUTHOR]

Clinical prediction models assist clinicians to estimate the natural course of a condition, and thus facilitate treatment decisions. The development of prediction models is increasingly common in obstetric research. Composite outcomes, whereby multiple outcomes are combined into a single endpoint, are frequently used in obstetric prediction models to increase statistical power when predicting rare events. Although existing literature has reviewed the positives and negatives of using composite outcomes in clinical trials, there has been minimal commentary on the implications of their use in the development and reporting of prognostic models. In this article, we review these issues, in particular, highlighting how unequal individual relationships between predictors and individual component outcomes can result in misleading conclusions, which may result in the omission of important but rare predictors or inappropriately inform clinical decisions to implement an intervention. We propose careful use, or where possible avoidance, of composite outcomes in the development of prognostic models in obstetrics. Methodological standards for developing prognostic models should be updated to standardise and appraise composite outcomes when their use is necessary. We also support previous recommendations to report on the accuracy of key components and inconsistencies among predictor variables. [ABSTRACT FROM AUTHOR]

Aim: In this study, we evaluated the effects of delivery time on maternal-fetal outcomes by evaluating patients who were taken to the gynecological intermediate intensive care unit according to their delivery hours. Materials and Methods: This study cohort included 292 women aged 18-45 years, whom we followed up in the postpartum gynecological intermediate intensive care unit. We divided the patients into three groups according to the time they gave birth. Those who gave birth between 08:00-16.00 formed group1, those who gave birth between 16:00-24:00 group2, and those who gave birth between 24:00-08:00 formed group 3. We compared all collected data between groups. Results: Hysterectomy (45(36%)) and blood transfusion (35(28%)) rates in the first group were higher than the other groups (p <0.001). Drain placement rates were higher in group 3 (48 (84.2%), p<0.001). No other operative approach and complications were significantly different between the three groups. Conclusion: Regarding maternal-fetal outcomes and surgical complications, making the delivery outside of working hours or after 24:00 may not have a negative effect. [ABSTRACT FROM AUTHOR]

Introduction: Bayesian adaptive designs for clinical trials have gained popularity in the recent years due to the flexibility and efficiency that they offer. We consider the scenario where the outcome of interest comprises events with relatively low risk of occurrence and different case definitions resulting in varying control group risk assumptions. This is a scenario that occurs frequently for infectious diseases in global health research. Methods: We propose a Bayesian adaptive design that incorporates different case definitions of the outcome of interest that vary in stringency. A set of stopping rules are proposed where superiority and futility may be concluded with respect to different outcome definitions and therefore maintain a realistic probability of stopping in trials with low event rates. Through a simulation study, a variety of stopping rules and design configurations are compared. Results: The simulation results are provided in an interactive web application that allows the user to explore and compare the design operating characteristics for a variety of assumptions and design parameters with respect to different outcome definitions. The results for select simulation scenarios are provided in the article. Discussion: Bayesian adaptive designs offer the potential for maximizing the information learned from the data collected through clinical trials. The proposed design enables monitoring and utilizing multiple composite outcomes based on rare events to optimize the trial design operating characteristics. [ABSTRACT FROM AUTHOR]

Originally proposed for the analysis of prioritized composite endpoints, the win ratio has now expanded into a broad class of methodology based on general pairwise comparisons. Complicated by the non‐i.i.d. structure of the test statistic, however, sample size estimation for the win ratio has lagged behind. In this article, we develop general and easy‐to‐use formulas to calculate sample size for win ratio analysis of different outcome types. In a nonparametric setting, the null variance of the test statistic is derived using U‐statistic theory in terms of a dispersion parameter called the standard rank deviation, an intrinsic characteristic of the null outcome distribution and the user‐defined rule of comparison. The effect size can be hypothesized either on the original scale of the population win ratio, or on the scale of a "usual" effect size suited to the outcome type. The latter approach allows one to measure the effect size by, for example, odds/continuation ratio for totally/partially ordered outcomes and hazard ratios for composite time‐to‐event outcomes. Simulation studies show that the derived formulas provide accurate estimates for the required sample size across different settings. As illustration, real data from two clinical studies of hepatic and cardiovascular diseases are used as pilot data to calculate sample sizes for future trials. [ABSTRACT FROM AUTHOR]

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Composite end points are common primary outcomes in clinical trials. Their main benefit of utilizing a composite outcome is increasing the number of primary outcome events, meaning fewer participants are required to deliver an adequately powered trial. By combining multiple important end points in the primary outcome rather than having to select only 1, composite end points potentially make clinically meaningful benefits easier to detect and avoid ranking outcomes hierarchically. However, there are a number of important considerations when designing and interpreting clinical trials that utilize composite end points. In this Statistical Primer, issues with composite end points such as competing events, halo effect, risk of bias, time-to-event limitations and the win ratio are discussed in the context of real world clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background Rheumatic mitral stenosis is a significant cause of valvular heart disease. Pulmonary arterial systolic pressure (PASP) reflects the hemodynamic consequences of mitral stenosis and is used to determine treatment strategies. However, PASP progression and expected outcomes based on PASP changes in patients with moderately severe mitral stenosis remain unclear. Methods and Results A total of 436 patients with moderately severe rheumatic mitral stenosis (valve area 1.0–1.5 cm2) were enrolled. Composite outcomes included all‐cause mortality and hospitalization for heart failure. Data‐driven phenotyping identified 2 distinct trajectory groups based on PASP progression: rapid (8.7%) and slow (91.3%). Patients in the rapid progression group were older and had more diabetes and atrial fibrillation than those in the slow progression group (all P40 mm Hg was independently associated with allocation to the rapid progression group (odds ratio, 4.95 [95% CI, 2.08–11.99]; P40 mm Hg.

Background: This systematic review and meta-analysis aims to assess composite and aggregate outcomes of observational studies in Crohn's disease and to evaluate whether the number and type of variables included affect the frequency of the outcome. Methods: MEDLINE [via PubMed], Scopus and Web of Science were searched to identify observational studies that enrolled patients with Crohn's disease and evaluated a composite or aggregate outcome. The proportion of patients achieving the outcome was determined and a random-effects meta-analysis was performed to evaluate how the frequency of each outcome varies according to the reporting of predefined variables. Results: From 10,257 identified records, 46 were included in the qualitative analysis and 38 in the meta-analysis. The frequency for composite and aggregate outcomes was 0.445 [95% confidence interval (CI): 0.389–0.501] and 0.140 (95% CI: 0.000–0.211), respectively. When comparing composite outcomes by number of included variables, the frequency was 0.271 (95% CI: 0.000–0.405) and 0.698 (95% CI: 0.651–0.746), for one and six variables, respectively. The frequency of the composite outcome varied according to the identity of the variables being reported. Specific pairs of predefined variables had a significant effect in the frequency of composite outcomes. Conclusion: Composite outcomes with increasing number of predefined variables show an increase in frequency. Outcomes including variables such as 'Surgery' and 'Steroids' had higher frequencies when compared with the ones that did not include these variables. These results show that the frequency of composite outcomes is dependent on the number and type of variables being reported. [ABSTRACT FROM AUTHOR]

Abstract Background Composite outcomes are increasingly being used in obstetric trials. The aim of this systematic review is to critically appraise the use of composite outcomes in obstetric RCTs with an intention of identifying limitations and providing potential solutions for future research. Methods The study protocol was prospectively registered. Medline, Embase, Cochrane Databases and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) published in English between 1999 and 2019, using search terms related to pregnancy and composite outcomes. Study eligibility criteria: RCTs involving an obstetric condition that reported on a composite outcome. Study appraisal and synthesis methods: Screening and data extraction were performed in duplicate, and a descriptive synthesis and critical appraisal of composite obstetric outcomes, is presented. Results Of the 4170 results screened, we identified 156 RCTs, reporting on 181 composite outcomes. Of these, 158 composite outcomes related to general morbidity and mortality, either exclusively maternal (n=20), fetal-neonatal [perinatal] (n=116) or maternal and perinatal (n=22) were included in the final analysis. Obstetric composite outcomes included between two and 16 components. Components that comprised these composite outcomes were often dissimilar in terms of severity and frequency of occurrence, unlikely to have similar relative risk reductions and sometimes unrelated to the study’s primary objective – important pre-requisites to consider while constructing composite outcomes. In addition, composite adverse obstetric outcomes often do not incorporate the perspectives of pregnant persons, embrace a holistic view of health or consider outcomes related to both members of the mother-fetus dyad. Conclusions Composite outcomes are being increasingly used as primary outcomes in obstetric RCTs, based on which study conclusions are drawn and clinical recommendations made. However, there is a lack of consistency with regard to what components should be included within a composite adverse obstetric outcome and how these components should be measured. The use of novel research methods such as concept mapping may be able to address some of the limitations with the development of composite adverse obstetric outcomes, to inform future research.

Rationale & Objective: Potential surrogate end points for kidney failure have been proposed in chronic kidney disease (CKD); however, they must be evaluated to ensure accurate, powerful, and harmonized research, particularly among patients with advanced CKD. The aim of the current study was to investigate the power and predictive ability of surrogate kidney failure end points in a population with moderate-to-advanced CKD. Study Design: Analysis of longitudinal data of a large multinational CKD observational study (Chronic Kidney Disease Outcomes and Practice Patterns Study). Setting & Participants: CKD stage 3-5 patients from Brazil, France, Germany, and the United States. Outcomes: Reaching an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 or eGFR decline of ≥40%, and composite end points of these individual end points. Analytical Approach: Each end point was used as a time-varying indicator in the Cox model to predict the time to kidney replacement therapy (KRT; dialysis or transplant) and was compared by the number of events and prediction accuracy. Results: 8,211 patients had a median baseline eGFR of 27 mL/min/1.73 m2 (interquartile range, 21-36 mL/min/1.73 m2) and 1,448 KRT events over a median follow-up of 2.7 years (interquartile range, 1.2-3.0 years). Among CKD stage 4 patients, the eGFR < 15 mL/min/1.73 m2 end point had higher prognostic ability than 40% eGFR decline, but the end points were similar for CKD stage 3 patients. The combination of eGFR < 15 mL/min/1.73 m2 and 40% eGFR decline had the highest prognostic ability for predicting KRT, regardless of the CKD stage. Including KRT in the composite can increase the number of events and, therefore, the power. Limitations: Variable visit frequency resulted in variable eGFR measurement frequency. Conclusions: The composite end point can be useful for CKD progression studies among patients with advanced CKD. Harmonized use of this approach has the potential to accelerate the translation of new discoveries to clinical practice by identifying risk factors and treatments for kidney failure.

Abstract Background Because of unknown features of the COVID-19 and the complexity of the population affected, standard clinical trial designs on treatments may not be optimal in such patients. We propose two independent clinical trials designs based on careful grouping of patient and outcome measures. Methods Using the World Health Organization ordinal scale on patient status, we classify treatable patients (Stages 3–7) into two risk groups. Patients in Stages 3, 4 and 5 are categorized as the intermediate-risk group, while patients in Stages 6 and 7 are categorized as the high-risk group. To ensure that an intervention, if deemed efficacious, is promptly made available to vulnerable patients, we propose a group sequential design incorporating four factors stratification, two interim analyses, and a toxicity monitoring rule for the intermediate-risk group. The primary response variable (binary variable) is based on the proportion of patients discharged from hospital by the 15th day. The goal is to detect a significant improvement in this response rate. For the high-risk group, we propose a group sequential design incorporating three factors stratification, and two interim analyses, with no toxicity monitoring. The primary response variable for this design is 30 day mortality, with the goal of detecting a meaningful reduction in mortality rate. Results Required sample size and toxicity boundaries are calculated for each scenario. Sample size requirements for designs with interim analyses are marginally greater than ones without. In addition, for both the intermediate-risk group and the high-risk group, the required sample size with two interim analyses is almost identical to analyses with just one interim analysis. Conclusions We recommend using a binary outcome with composite endpoints for patients in Stage 3, 4 or 5 with a power of 90% to detect an improvement of 20% in the response rate, and a 30 day mortality rate outcome for those in Stage 6 or 7 with a power of 90% to detect 15% (effect size) reduction in mortality rate. For the intermediate-risk group, two interim analyses for efficacy evaluation along with toxicity monitoring are encouraged. For the high-risk group, two interim analyses without toxicity monitoring is advised.

Introduction: Composite outcomes are used to increase the power of a study by combining event rates. Many composite outcomes in adult clinical trials have components that differ substantially in patient importance, event rate, and effect size, making interpretation challenging. Little is known about the use of composite outcomes in neonatal randomized controlled trials (RCTs). Methods: We assessed the use of composite outcomes in neonatal RCTs included in Cochrane Neonatal reviews published till November 2017. Two authors reviewed the components of the composite outcomes to compare their patient importance and computed the ratios of effect sizes and event rates between the components, with an a priori threshold of 1.5, indicating a substantial difference. Descriptive statistics were presented. Results: We extracted 7,766 outcomes in 2,134 RCTs in 312 systematic reviews. Among them, 55 composite outcomes (0.7%) were identified in 46 RCTs. The vast majority (92.7%) of composite outcomes had 2 components, with death being the most common component (included 51 times [92.7%]). The components in nearly three-quarters of the composite outcomes (n = 40 [72.7%]) had different patient importance, while the effect sizes and event rates differed substantially between the components in 27 (49.1%) and 35 (63.6%) outcomes, respectively, with up to 43-fold difference in the event rates observed. Conclusions: The majority of composite outcomes in neonatal RCTs had different patient importance with contrasting effect sizes and event rates between the components. In patient communication, clinicians should highlight individual components, rather than the composites, with explanation on the relationship between the components, to avoid misleading impression on the effect of the intervention. Future trials should report the estimates of all individual components alongside the composite outcomes presented. [ABSTRACT FROM AUTHOR]

Background: Composite outcomes are increasingly being used in obstetric trials. The aim of this systematic review is to critically appraise the use of composite outcomes in obstetric RCTs with an intention of identifying limitations and providing potential solutions for future research.Methods: The study protocol was prospectively registered. Medline, Embase, Cochrane Databases and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) published in English between 1999 and 2019, using search terms related to pregnancy and composite outcomes.Study Eligibility Criteria: RCTs involving an obstetric condition that reported on a composite outcome.Study Appraisal and Synthesis Methods: Screening and data extraction were performed in duplicate, and a descriptive synthesis and critical appraisal of composite obstetric outcomes, is presented.Results: Of the 4170 results screened, we identified 156 RCTs, reporting on 181 composite outcomes. Of these, 158 composite outcomes related to general morbidity and mortality, either exclusively maternal (n=20), fetal-neonatal [perinatal] (n=116) or maternal and perinatal (n=22) were included in the final analysis. Obstetric composite outcomes included between two and 16 components. Components that comprised these composite outcomes were often dissimilar in terms of severity and frequency of occurrence, unlikely to have similar relative risk reductions and sometimes unrelated to the study's primary objective - important pre-requisites to consider while constructing composite outcomes. In addition, composite adverse obstetric outcomes often do not incorporate the perspectives of pregnant persons, embrace a holistic view of health or consider outcomes related to both members of the mother-fetus dyad.Conclusions: Composite outcomes are being increasingly used as primary outcomes in obstetric RCTs, based on which study conclusions are drawn and clinical recommendations made. However, there is a lack of consistency with regard to what components should be included within a composite adverse obstetric outcome and how these components should be measured. The use of novel research methods such as concept mapping may be able to address some of the limitations with the development of composite adverse obstetric outcomes, to inform future research. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the frequency and critically appraise the use and reporting of composite outcomes in randomized clinical trials on pharmacological interventions for coronary artery disease., Study Design and Setting: A metaresearch study. A search strategy was developed to retrieve references from MEDLINE. We considered articles, published from 1st January 2020, to December 31, 2021, reporting results of clinical primary outcomes from randomized clinical trials which assessed pharmacological interventions, used alone or in combination, for the treatment or secondary prevention (previous coronary event) of coronary artery disease., Results: From the 34 included studies, 28 (82.35%) had a primary composite outcome. Thirteen unique composite primary outcomes were used with the most frequent being "cardiovascular death, myocardial infarction, stroke" (12/28, 42.86%). The term major adverse cardiac events was used for five distinct composite primary outcomes. A combination of 12 different components resulted in the 28 primary composite outcomes, with stroke being the most frequent component present in 96.43% (27/28) of the primary composite outcomes. From the included studies, 60.71% (17/28) reported the estimates for each individual component and the direction of the effect was consistent between all components and the composite outcomes in 58.82% (10/17) of them. Additionally, no included study discussed potential limitations and/or related advantages of the composite outcomes., Conclusion: In randomized clinical trials on pharmacological interventions for coronary artery disease, composite outcomes are frequently used, but the definition of their components is very heterogeneous. The estimate for individual components within the composite outcome is often not fully reported, which prevents a complete analysis of their adequacy for clinical practice. The term major adverse cardiac events was used inconsistently and to refer to different set of components, which can also be misleading and confusing., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract Introduction Composite scales have been advanced as primary outcomes in early stage Alzheimer's disease trials, and endorsed by the U.S. Food and Drug Administration (FDA) for pivotal trials. They are generally composed of several neurocognitive subscales and may include clinical and functional activity scales. Methods We summarized the development of 12 composite scales intended as outcomes for clinical trials and assessed their characteristics. Results Composite scales have been constructed from past observational and clinical trial databases by selecting components of individual neuropsychological tests previously used in clinical trials. The atheoretical approaches to combining scales into a composite scale that have often been used risk omitting clinically important measures and so may include redundant, irrelevant, or noncontributory tests. The deliberate combining of neurocognitive scales with functional activity scales provides arbitrary weightings that also may be clinically irrelevant or obscure change in a particular domain. Basic psychometric information is lacking for most of the composites. Discussion Although composite scales are desirable for pivotal clinical trials because they, in principle, provide for a single, primary outcome combining neurocognitive and/or functional domains, they have substantial limitations, including their common derivations, inattention to basic psychometric principles, redundancy, absence of alternate forms, and, arguably, the inclusion of functional measures in some. In effect, any currently used composite is undergoing validation through its use in a trial. The assumption that a composite, by its construction alone, is more likely than an individual measure to detect an effect from any particular drug and that the effect is more clinically relevant or valid has not been demonstrated.

Abstract Background Hospital mortality, readmission and length of stay (LOS) are commonly used measures for quality of care. We aimed to disentangle the correlations between these interrelated measures and propose a new way of combining them to evaluate the quality of hospital care. Methods We analyzed administrative data from the Global Comparators Project from 26 hospitals on patients discharged between 2007 and 2012. We correlated standardized and risk-adjusted hospital outcomes on mortality, readmission and long LOS. We constructed a composite measure with 5 levels, based on literature review and expert advice, from survival without readmission and normal LOS (best) to mortality (worst outcome). This composite measure was analyzed using ordinal regression, to obtain a standardized outcome measure to compare hospitals. Results Overall, we observed a 3.1% mortality rate, 7.8% readmission rate (in survivors) and 20.8% long LOS rate among 4,327,105 admissions. Mortality and LOS were correlated at the patient and the hospital level. A patient in the upper quartile LOS had higher odds of mortality (odds ratio = 1.45, 95% confidence interval 1.43–1.47) than those in the lowest quartile. Hospitals with a high standardized mortality had higher proportions of long LOS (r = 0.79, p

Acute kidney injury (AKI) is associated with high mortality in burn patients. Urinary biomarkers can aid in the prediction of AKI and its consequences, such as death and the need for renal replacement therapy (RRT). The purpose of this study was to investigate a novel methodology for detecting urinary biomarkers, the NephroCheck® Test System, and assess its ability to predict death or the need for RRT in burn patients. Burn patients admitted to the United States Army Institute of Surgical Research (USAISR) burn intensive care unit were prospectively enrolled between March 2016 and April 2018. A urine sample was obtained from all study participants using the NephroCheck® system. Patient and injury characteristics were gathered, and descriptive statistics were calculated and multivariable logistic regression analyses were performed using these data. Of the 69 patients in this study, 15 patients (21.7%) attained the composite outcome of death or needing RRT within 30 days of urine collection. NephroCheck® scores were higher for patients with the composite outcome, with P = 0.06 for centrifuged scores and P = 0.04 for noncentrifuged scores. Centrifuged and noncentrifuged scores were in high agreement and correlation (R2 = 0.97, P < 0.0001). Noncentrifuged scores were significant in the unadjusted analysis, but they were not significant in the adjusted analysis. Although these scores had a lower sensitivity and negative predictive value compared with other parameters, they had the second highest specificity and positive predictive value. NephroCheck® scores were higher in burn patients with the composite outcome of death or needing RRT, and they demonstrated comparable sensitivity and specificity to creatinine and TBSA. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus bacteraemia (SAB) management bundles have been shown to improve performance measures and clinical outcomes. SAB bundles often require direct intervention by infectious diseases (ID) physicians or antibiotic stewardship programme (ASP) members or pharmacists. The purpose of this study was to evaluate an automated, real-time ASP intervention utilizing clinical decision support (CDS) in the electronic health record (EHR) for the management of SAB.Methods: A retrospective, single-centre quasi-experimental study of hospitalized patients with known SAB was conducted. The intervention was the implementation of a hard-stop best practice advisory (BPA) alert that would prompt physicians to use an electronic order set, on identification of SAB, with management recommendations, including ID consultation. The primary outcome was overall adherence to six institutional ASP SAB bundle elements. Secondary outcomes included both clinical and process outcomes.Results: A total of 227 patients were included, 111 in the pre-intervention and 116 in the post-intervention period. Completion of all six bundle elements improved by 27.2% in the post-intervention group (29.7% versus 56.9%, P < 0.001). BPA activation and order-set utilization occurred in 95.7% and 57.8% in the post-intervention group, respectively. Composite outcome of 30 day mortality or 90 day readmission with SAB complication decreased in the post-intervention group by 9.6% (24.3% versus 14.7%, P = 0.092).Conclusions: Optimization of CDS within the EHR, using real-time BPA alert and order set, demonstrated an immediate, sustainable intervention that improved adherence to institutional performance measures for SAB management without direct prospective audit with intervention and feedback. [ABSTRACT FROM AUTHOR]

Objectives: Survival from acute respiratory distress syndrome is improving, and outcomes beyond mortality may be important for testing new treatments. The "ventilator-free days" score, is an established composite that equates ventilation on day 28 to death. A hierarchical outcome treating death as a worse than prolonged ventilation would enhance face validity, but performance characteristics and reporting of such an outcome are unknown. We therefore evaluated the performance of a novel hierarchical composite endpoint, the Alive and Ventilator Free score.Design: Using data from four Acute Respiratory Distress Syndrome Network clinical trials, we compared Alive and Ventilator Free to the ventilator-free days score. Alive and Ventilator Free compares each patient with every other patient in a win-lose-tie for each comparison. Duration of mechanical ventilation is only compared if both patients survived. We evaluated power of Alive and Ventilator Free versus ventilator-free days score under various circumstances.Setting: ICUs within the Acute Respiratory Distress Syndrome Network.Patients: Individuals enrolled in four Acute Respiratory Distress Syndrome Network trials.Interventions: None for this analysis.Measurements and Main Results: Within the four trials (n = 2,410 patients), Alive and Ventilator Free and ventilator-free days score had similar power, with Alive and Ventilator Free slightly more powerful when a mortality difference was present, and ventilator-free days score slightly more powerful with a difference in duration of mechanical ventilation. Alive and Ventilator Free less often found in favor of treatments that increased mortality and increased days free of ventilation among survivors.Conclusions: A hierarchical composite endpoint, Alive and Ventilator Free, preserves statistical power while improving face validity. Alive and Ventilator Free is less prone to favor a treatment with discordant effects on survival and days free of ventilation. This general approach can support complex outcome hierarchies with multiple constituent outcomes. Approaches to interpretation of differences in Alive and Ventilator Free are also presented. [ABSTRACT FROM AUTHOR]

Background: Composite outcomes, which combine multiple types of clinical events into a single outcome, are common in clinical trials. The usual analysis considers the time to first occurrence of any event in the composite. The major criticisms of such an approach are (1) this implicitly treats the outcomes as if they were of equal importance, but they often vary in terms of clinical relevance and severity, (2) study participants often experience more than one type of event, and (3) often less severe events occur before more severe ones, but the usual analysis disregards any information beyond that first event. Methods: A novel approach, referred to as the win ratio, which addresses the aforementioned criticisms of composite outcomes, is illustrated with a re-analysis of data on fatal and non-fatal cardiovascular disease time-to-event outcomes reported for the Multiple Risk Factor Intervention Trial. In this trial, 12,866 participants were randomized to a special intervention group (n = 6428) or a usual care (n = 6438) group. Non-fatal outcomes were ranked by risk of cardiovascular disease death up to 20 years after trial. In one approach, participants in the special intervention and usual care groups were first matched on coronary heart disease risk at baseline and time of enrollment. Each matched pair was categorized as a winner or loser depending on which one experienced a cardiovascular disease death first. If neither died of cardiovascular disease causes, they were evaluated on the most severe non-fatal outcome. This process continued for all the non-fatal outcomes. A second win ratio statistic, obtained from Cox partial likelihood, was also estimated. This statistic provides a valid estimate of the win ratio using multiple events if the marginal and conditional survivor functions of each outcome satisfy proportional hazards. Loss ratio statistics (inverse of win ratios) are compared to hazard ratios from the usual first event analysis. A larger 11-event composite was also considered. Results: For the 7-event cardiovascular disease composite, the previously reported first event analysis based on 581 events in the special intervention group and 652 events in the usual care group yielded a hazard ratio (95% confidence interval) of 0.89 (0.79–0.99), compared to 0.86 (0.77–0.97) and 0.91 (0.81–1.02) for the severity ranked estimates. Results for the 11-event composite also confirmed the findings of the first event analysis. Conclusion: The win ratio analysis was able to leverage information collected past the first experienced event and rank events by severity. The results were similar to and confirmed previously reported traditional first event analysis. The win ratio statistic is a useful adjunct to the traditional first event analysis for trials with composite outcomes. [ABSTRACT FROM AUTHOR]

Objective: Spinal cord stimulation (SCS) is effective for relieving chronic intractable pain conditions. The Dorsal spInal cord STImulatioN vs mediCal management for the Treatment of low back pain study evaluates the effectiveness of SCS compared with conventional medical management (CMM) in the treatment of chronic low back pain in patients who had not undergone and were not candidates for lumbar spine surgery., Methods and Materials: Patients were randomized to passive recharge burst therapy (n = 162) or CMM (n = 107). They reported severe pain and disability for more than a decade and had failed a multitude of therapies. Common diagnoses included degenerative disc disease, spondylosis, stenosis, and scoliosis-yet not to a degree amenable to surgery. The six-month primary end point compared responder rates, defined by a 50% reduction in pain. Hierarchical analyses of seven secondary end points were performed in the following order: composite responder rate (numerical rating scale [NRS] or Oswestry Disability Index [ODI]), NRS, ODI, Pain Catastrophizing Scale responder rate, Patient Global Impression of Change (PGIC) responder rate, and Patient-Reported Outcome Measure Information System-29 in pain interference and physical function., Results: Intention-to-treat analysis showed a significant difference in pain responders on NRS between SCS (72.6%) and CMM (7.1%) arms (p < 0.0001). Of note, 85.2% of those who received six months of therapy responded on NRS compared with 6.2% of those with CMM (p < 0.0001). All secondary end points indicated the superiority of burst therapy over CMM. A composite measure on function or pain relief showed 91% of subjects with SCS improved, compared with 16% of subjects with CMM. A substantial improvement of 30 points was observed on ODI compared with a

Aims: Lead perforation is a rare, well-known complication of cardiac implantable electronic device (CIED) implants, whose management is mostly not evidence-based. Main management strategies include conservative approach based on clinical and lead function follow-up vs. routine invasive lead revision approach. This study compared the complications of both strategies by composite endpoint, including recurrent perforation-related symptoms, recurrent pericardial effusion (PEf), lead dysfunction, and device infection during 12 month follow-up.Methods and Results: Multicentre retrospective analysis, inquiring data from imaging studies, device interrogation, pericardiocentesis, and clinical charts of patients with suspected perforating leads between 2007 and 2014 in five hospitals. All cases were reviewed by electrophysiologist and defined as definite perforations by suggestive symptoms along with lead perforation on imaging, bloody PEf on pericardiocentesis shortly after implant, or right ventricular (RV) lead non-capture along with diaphragmatic stimulation upon bipolar pacing. Clinical outcomes associated with both management approaches were compared, with respect to the composite endpoint. The study included 48 definitive perforation cases: 22 managed conservatively and 26 via lead revision. Conservative management was associated with an increased composite endpoint compared with lead revision (8/22 vs. 1/26; P = 0.007). The dominant complication among the conservative cohort was appearance of cardiac tamponade during follow-up; 5/6 occurring in cases which presented with no or only mild PEf and were treated by antiplatelets/coagulants during or shortly after CIED implantation.Conclusion: A conservative management of CIED lead perforation is associated with increased complications compared with early lead revision. Lead revision may be the preferred management particularly in patients receiving antiplatelets/coagulants. [ABSTRACT FROM AUTHOR]

Background Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. Methods In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the "Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. Results In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. Conclusion This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study. [ABSTRACT FROM AUTHOR]

Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. All trials assessed pain intensity on a 0 to 10 numeric rating scale and physical function with the 10-item subscale of the Short Form-36, ranging 0 to 100 with higher scores indicating better function. Correlation between change in pain intensity from baseline to posttreatment and change in physical function was small in DPN (ρ = -0.22; P < 0.001) and nonsignificant in PHN (ρ = -0.05; P = 0.08). Assay sensitivities of 10 composite outcomes were examined in a random subsample of patients enrolled in pregabalin trials for DPN and PHN. Of these, a responder outcome of ≥50% improvement in pain intensity, or a ≥20% improvement in pain intensity and ≥30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross-validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of ≥50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials. [ABSTRACT FROM AUTHOR]

The military has used silver-nylon dressings as a topical antimicrobial on combat-related burns for the past 15 years. However, their clinical efficacy and associated risks have not been evaluated. Herein, the authors document our experience with the use of a specific silver-nylon dressing (Silverlon®) during global evacuation of casualties from combat zones to the United States sArmy Institute of Surgical Research Burn Center. A 10-year retrospective analysis was performed. Variables included patient demographics, total body surface area, length of stay, Injury Severity Score, incidence of urinary tract and burn infections, pneumonia, patient status at the time of discharge, and a composite endpoint. The patient cohort was stratified into two groups: Silverlon® (Group 1) and topical antimicrobial agents (Group 2). Data were analyzed using appropriate statistical tests (P ≤ .05). Nine hundred eighty-eight patients (26 ± 6 years) were identified with 184 patients (Group 1) and 804 patients (Group 2). Silver-nylon dressings trended toward decreased wound infection rate (5.4 vs 9.5%) even when applied to full-thickness burn injuries. When compared with topical antimicrobial agents, the silver-nylon dressing was not associated with significant differences in burn-related complication. The authors demonstrate the antimicrobial efficacy of the silver-nylon dressing during global evacuation of burn casualties from combat zones to the burn center. Compared with topical antimicrobials, the silver-nylon dressing is lightweight and easy to apply and requires minimal wound management which makes it desirable as a burn dressing for combat applications as well as mass casualty situations. [ABSTRACT FROM AUTHOR]