Endpoint Definitions Research Articles

Discharge Location and Outcomes After Transcatheter Aortic Valve Implantation

The relation between discharge location and outcomes after transcatheter aortic valve implantation (TAVI) is largely unknown. Thus, the objective of this study was to investigate the impact of discharge location on clinical outcomes after TAVI. Between August 2007 and December 2018, consecutive patients who underwent transfemoral TAVI at Bern University Hospital were grouped according to discharge location. Clinical adverse events were adjudicated according to VARC-2 end point definitions. Of 1,902 eligible patients, 520 (27.3%) were discharged home, 945 (49.7%) were discharged to a rehabilitation clinic and 437 (23.0%) were transferred to another institution. Compared with patients discharged to a rehabilitation facility or another institution, patients discharged home were younger (80.8 ± 6.5 vs 82.9 ± 5.4 and 82.8 ± 6.4 years), less likely female (37.3% vs 59.7% and 54.2%), and at lower risk according to STS-PROM (4.5 ± 3.0% vs 5.5 ± 3.8% and 6.6 ± 4.4%). At 1 year follow-up, patients discharged home had similar rates of all-cause mortality (HRadj 0.82; 95% CI 0.54 to 1.24), cerebrovascular events (HRadj 1.04; 95% CI 0.52 to 2.08) and bleeding complications (HRadj 0.93; 95% CI 0.61 to 1.41) compared with patients discharged to a rehabilitation facility. Patients discharged home or to rehabilitation were at lower risk for death (HRadj 0.37; 95% CI 0.24 to 0.56 and HRadj 0.44; 95% CI 0.32 to 0.60) and bleeding (HRadj 0.48; 95% CI 0.30 to 0.76 and HRadj 0.66; 95% CI 0.45 to 0.96) during the first year after hospital discharge compared with patients transferred to another institution. In conclusion, discharge location is associated with outcomes after TAVI with patients discharged home or to a rehabilitation facility having better clinical outcomes than patients transferred to another institution. Clinical Trial Registration: https://www.clinicaltrials.gov. NCT01368250.

TAVI durability

Abstract Background TAVI (Transcatheter aortic valve implantation) is now established as the preferred treatment option for patients with symptomatic severe aortic stenosis at prohibitive or high surgical risk and its application is increasingly supported by an accumulating evidence base in patients at intermediate and low risk, but the issue of valve durability are still unsettled. Purpose To evaluate long-term clinical outcomes and bioprosthesis valve dysfunction after TAVI. Methods All patients treated with transfemoral TAVI, from November 2007 to December 2014 were analyzed. Baseline clinical, procedural and in-hospital outcomes were collected and revised. Clinical and echocardiographic follow-up was conducted either by clinic visits or telephone consultations. All definitions of the clinical endpoints and bioprosthesis valve failure used were in concordance with the Valve Academic Research Consortium 2 and the European Society of Cardiology consensus, respectively. Results Four hundred and eight patients were included in the analysis. Median follow-up was 2.733 days (7.5 years), with the longest follow-up at 4.096 days (11.2 years). At 7.5 years (IQR 5.4–9.3 years), all-cause mortality was 64.5% (n=263), of these cardiovascular death was adjudicated in 33.6% (n=137), non-cardiovascular death in 30.9% (n=126) and valve-related death was 1.9% (n=8). Structural valve deterioration occurred in 2.9% (n=12), non-structural valve deterioration in 0.2% (n=1), thrombosis in 2.2% (n=9) and endocarditis in 3.2% of patients (n=13). Fourteen patients (3.4%) required surgical (1.2%) or percutaneous (2.2%) aortic valve re-intervention. Conclusions Percutaneous aortic bioprosthesis demonstrated a low bioprosthesis valve failure at a median of 7.5 years of clinical follow-up after implantation, with low rate of degeneration or need of re-intervention. Overall mortality was high with acceptable rates of cardiovascular mortality and low rates of valve-related deaths. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): EAPCI Education and Training Grants

The prognostic value of platelet-to-lymphocyte ratio on the long-term renal survival in patients with IgA nephropathy

PurposePlatelet-to-lymphocyte ratio (PLR) was established showing the poor prognosis in several diseases, such as malignancies and cardiovascular diseases. But limited study has been conducted about the prognostic value of PLR on the long-term renal survival of patients with Immunoglobulin A nephropathy (IgAN).MethodsWe performed an observational cohort study enrolling patients with biopsy-proven IgAN recorded from November 2011 to March 2016. The definition of composite endpoint was eGFR decrease by 50%, eGFR < 15 mL/min/1.73 m2, initiation of dialysis, or renal transplantation. Patients were categorized by the magnitude of PLR tertiles into three groups. The Kaplan–Meier curves and multivariate Cox models were performed to determine the association of PLR with the renal survival of IgAN patients.Results330 patients with a median age of 34.0 years were followed for a median of 47.4 months, and 27 patients (8.2%) had reached the composite endpoints. There were no differences among the three groups (PLR < 106, 106 ≤ PLR ≤ 137, and PLR > 137) in demographic characteristics, mean arterial pressure (MAP), proteinuria, and estimated glomerular filtration rate (eGFR) at baseline. The Kaplan–Meier curves showed that the PLR > 137 group was significantly more likely to poor renal outcomes than the other two groups. Using univariate and multivariate cox regression analyses, we found that PLR > 137 was an independent prognostic factor for poor renal survival in patients with IgAN. Subgroup analysis revealed that the PLR remained the prognostic value for female patients or patients with eGFR less than 60 mL/min/1.73 m2.ConclusionsOur results underscored that baseline PLR was an independent prognostic factor for poor renal survival in patients with IgAN, especially for female patients or those patients with baseline eGFR less than 60 mL/min/1.73 m2.

Adjudication Of Cause-specific Endpoints In Heart Failure Trials

Introduction Clinical endpoints are standard outcomes measures used to prove treatment effect in clinical trials. Differences in endpoint definitions and ascertainment of cause-specific clinical events influence the validity of heart failure (HF) trials. Cause-specific clinical events have become preferred endpoints because they separate signals of efficacy from noise (non-related events). Clinical endpoints could be ascertained through case report forms (CRFs) by investigators or through a central adjudication method by a Clinical Endpoint Committee (CEC). Investigator reporting is more efficient and inexpensive but is affected by inaccuracy, geographic variability, and complexity of endpoint definitions. CEC adjudication is a standardized, blind and independent ascertainment process but may be limited by high costs. Aims To analyze cause-specific endpoints, and the need for CEC adjudication in HF trials, comparing HF with reduced versus preserved ejection fraction (EF). Methods We analyzed 10 HF with reduced EF (HFrEF) trials and five HF with preserved EF (HFpEF) trials. For each trial we described and compared the prevalence of all-cause and cause-specific mortality. Results A comparison between all-cause mortality and cardiovascular mortality in 9 selected HFrEF and HFpEF clinical trials is presented in Figure 1. The relative proportion of CV death was significantly lower in HFpEF compared with HFrEF trials. Additionally, in HFrEF, the relative proportion of CV death was significantly lower in recent trials compared with early trials. CV specific endpoints were the primary cause of death in HF trials. Conclusions There are more CV deaths in HFrEF trials, although it is the primary mode of death in both populations. CEC adjudication may be more beneficial in HFpEF vs. HFrEF trials, and in recent HFrEF trials due to the increase in non-CV events which may attenuate the treatment effect.

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Lower Drug Cost of Successfully Treating Patients with Type 2 Diabetes to Targets with Once-Weekly Semaglutide versus Once-weeklyDulaglutide in Japan: A Short-Term Cost-Effectiveness Analysis.

In the head-to-head trial (SUSTAIN 7), the novel, injectable, once-weekly GLP-1 analogue semaglutide showed superiority in both glycemic outcomes and body weight reduction, compared with once-weeklydulaglutide in the treatment of type 2 diabetes (T2D). However, no economic evaluation using these data has yet been conducted in the Japanese setting. The objective of this analysis was to assess the short-term cost-effectiveness in Japan of once-weekly semaglutide 0.5mg (the approved maintenance dose in Japan) compared withonce-weekly dulaglutide 0.75mg (the only licensed dose in Japan) over a 1-year period using Japanese cost data. Responder endpoints were obtained from the SUSTAIN 7 trial to assess the cost of successfully treating patients to these targets ("cost of control"). Responder endpoint definitions consisted of single, dual, and triple composite endpoints related to glycemic control, body weight, and hypoglycemia outcomes. The cost of treatment was accounted from a healthcare payer perspective, capturing drug costs only. Treatment with once-weekly semaglutide 0.5mg was associated with a lower cost and a lower cost per patient treated to target for all endpoints, compared with once-weeklydulaglutide 0.75mg. For each JPY1 spent on bringing patients to target with once-weekly semaglutide 0.5mg, JPY1.58, JPY1.44, JPY1.60, JPY2.10, and JPY2.33 would need to be spent on once-weeklydulaglutide 0.75mg to achieve an equivalent outcome for endpoints of HbA1c ≤ 6.5%, HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia, and no weight gain, weight loss ≥ 5%, and ≥ 1.0% HbA1c reduction and ≥ 3.0% weight loss, respectively. These findings suggest that once-weekly semaglutide is a cost-effective treatment option compared withonce-weekly dulaglutide for patients with T2D in Japan. In the future, this finding should be extrapolated to traditional long-term cost-effectiveness analysis, using common outcomes such as quality-adjusted life years.

Clinical features and outcome of patients with chronic pulmonary aspergillosis in China: A retrospective, observational study

Chronic pulmonary aspergillosis (CPA) is a confusing respiratory disease, with many fundamental questions unanswered. We retrospectively evaluated the clinical characteristics, treatment, and outcome of patients with CPA in a tertiary hospital in China. Forty-six patients with CPA, including 26 patients with chronic cavitary pulmonary aspergillosis (CCPA), 13 patients with subacute invasive pulmonary aspergillosis (SAIA) and 7 patients with simple pulmonary aspergilloma (SA), were diagnosed from January 2014 to December 2017. A total of 18 patients with CCPA and 8 patients with SAIA had completed triazole treatment. Patients with SAIA had lower body mass index than patients with CCPA (18.9 vs. 20.4, P=0.011), and SAIA most frequently occurred in systematic diseases (62.5% vs. 11.1%, P=0.014). The medians of white blood count and C-reactive protein in patients with SAIA were higher than those in patients with CCPA (P<0.001). No significant difference was observed in the median of duration of treatment between patients with CCPA and SAIA (36.5weeks vs. 27.5weeks, P=0.144). Based on a composite of clinical, radiological, and mycological criteria, global success was observed in 12 patients with CCPA (66.7%) and 6 patients with SAIA (75.0%) at the end of the treatment. During the 1-year follow-up, 9 of 26 patients with CPA (34.6%) had a relapse. To date, we face a tremendous lack of evidence on CPA, and no commonly accepted treatment endpoint definition has been defined. In the future, collaborative research activities are needed to meet these challenges.

Patients' Understanding of Oncology Clinical Endpoints: Environmental Scan and Focus Groups.

Understanding treatment options is important for patients with cancer and their caregivers. This may be difficult, however, because oncology treatments are often approved based on complex clinical endpoints. The study aimed to explore lay understanding of oncology clinical endpoints by assessing the definitions of clinical endpoints available online and gathering qualitative focus group data on cancer survivors' and the general public's understanding of clinical endpoints. We conducted an environmental scan to find Web sites accessible by a general audience that defined three clinical endpoints: overall survival, progression-free survival, and response rate. Next, we conducted a series of eight focus groups across the U.S. with cancer survivors (n = 36) and general population adults (n = 36). We found several online resources defining each endpoint; however, many of the definitions we identified used technical language that may not be easily understood by patients and caregivers. Few focus group participants were familiar with the technical terms for these endpoints. When presented with the endpoint terms and definitions, participants had misconceptions about treatment efficacy. Specifically, they tended to expect that all endpoints were a variation on living longer. The results point to the need for more patient-friendly definitions of clinical endpoints developed with input from the general public and from patients with cancer. As the number of oncology prescription drug approvals and the advertising of those drugs to consumers increase, it is timely and critical to understand how to discuss treatment benefits with patients. Patient-friendly definitions of common clinical endpoints, such as overall survival and progression-free survival, would help health care providers describe treatment benefits to patients. This research provides evidence regarding patients' understanding of these endpoints and suggests definitions for additional research. This represents a first step in creating evidence-based patient-friendly language to describe clinical endpoints.

The mechanistic rationale of drugs, primary endpoints, geographical distribution of clinical trials against severe acute respiratory syndrome-related coronavirus-2: A systematic review.

There are numerous ongoing studies assessing treatment options for preventing, treating, and managing complications of coronavirus disease‐2019 disease. The objective of this study was to do a systematic review and critical appraisal of the ongoing clinical trials with an aim to provide insight into the various interventions tested, clinical rationale, geographical distribution of the trials as well as the endpoints assessed in the studies. ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and PubMed were assessed till 11 May 2020. The search resulted in 3242 ongoing studies of which 829 studies were included. There are 134 different drug‐based interventions being assessed in 463 clinical trials as treatment options China accounts for 35% of all ongoing clinical studies followed by USA 23% and other countries together account for 42%. Amongst the 463 studies assessing drug‐based treatment options, studies that are funded by federal and academic institutions are 79.6%, pharmaceutical company‐funded studies are 15.11%, and no funding information is available in 5.10%. The definitive outcomes like mortality are being assessed as primary outcome in 22.8% of the studies only and need for ventilator in 6.2% of the studies. Amongst the pharmaceutical company‐funded drug‐based studies, only 20% of the studies had mortality as the primary outcome. Only 5.5% of the ongoing clinical trials are specifically designed to assess the most vulnerable population like elderly, patients with comorbidities and cancer. Multiple intervention‐based clinical studies against severe acute respiratory syndrome‐related coronavirus‐2 are being performed throughout the world with a high concentration of clinical trials in the developed world with concern that of elderly and patients with comorbidities are being underrepresented and definite endpoints like mortality are being assessed in only one‐fifth of the studies.

Definition and severity grading of postoperative lymphatic leakage following inguinal lymph node dissection

PurposeLymphatic complications occur frequently after radical inguinal lymph node dissection (RILND). The incidence of lymphatic leakage varies considerably among different studies due to the lack of a consistent definition. The aim of the present study is to propose a standardized definition and grading of different types of lymphatic leakage after groin dissection.MethodsA bicentric retrospective analysis of 82 patients who had undergone RILND was conducted. A classification of postoperative lymphatic leakage was developed on the basis of the daily drainage output, any necessary postoperative interventions and reoperations, and any delay in adjuvant treatment.ResultsIn the majority of cases, RILND was performed in patients with inguinal metastases of malignant melanoma (n = 71). Reinterventions were necessary in 15% of the patients and reoperations in 32%. A new classification of postoperative lymphatic leakage was developed. According to this definition, grade A lymphatic leakage (continued secretion of lymphatic fluid from the surgical drains without further complications) occurred in 13% of the patients, grade B lymphatic leakage (persistent drainage for more than 10 postoperative days or the occurrence of a seroma after the initial removal of the drain that requires an intervention) in 28%, and grade C lymphatic leakage (causing a reoperation or a subsequent conflict with medical measures) in 33%. The drainage volume on the second postoperative day was a suitable predictor for a complicated lymphatic leakage (grades B and C) with a cutoff of 110 ml.ConclusionThe proposed definition is clinically relevant, is easy to employ, and may serve as the definition of a standardized endpoint for the assessment of lymphatic morbidity after RILND in future studies.

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.

Association of End Point Definition and Randomized Clinical Trial Duration in Clinical Trials of Schizophrenia Medications

Facilitating the development of safe and effective medications for schizophrenia is a public health imperative. To evaluate the association of shortening randomized clinical trial (RCT) duration with the modification of the Positive and Negative Syndrome Scale (PANSS) for the design of RCTs of medications for schizophrenia and to offer perspective on an alternative regulatory pathway to the historically accepted trial duration and response assessment. A database was created consisting of clinical trial data from 32 placebo-controlled RCTs of 8 atypical antipsychotic drugs approved by the US Food and Drug Administration (FDA) between January 1, 2001, and December 31, 2015. The database included information on total and individual PANSS item ratings, demographic characteristics, disposition, and adverse events (AEs). All clinical trials submitted to 8 new drug applications of atypical antipsychotic drugs were selected. Quality control checks were performed to ensure that the collected data were consistent with the reported results of each trial. Data were collected from March 15, 2015, to September 30, 2015. Data analysis was conducted from October 1, 2015, to June 20, 2016. The following analyses were performed: (1) longitudinal assessment of mean change from baseline in total PANSS score, (2) correlation analyses between change from baseline in total PANSS score at week 6 and earlier time points, (3) concordance analyses of outcomes across trials between week 6 and earlier time points using total PANSS and modified PANSS, and (4) analyses of time course of treatment-emergent AEs. The final database contained data from 14 219 participants enrolled in 32 drug trials; 9805 of 14 219 participants (69.0%) were male and were either white (7183 [50.5%]) or black (4346 [30.6%]) individuals. The mean (SD) age during treatment was 38.9 (10.9) years, and the mean (SD) age at schizophrenia diagnosis was 25 (8.5) years. Statistically significant separation between treatment response and placebo response was observed after 1 week of treatment. The overall concordance rate across treatment groups steadily increased from week 1 to week 4 (68.0% for week 1, 74.0% for week 2, 83.0% for week 3, and 93.0% for week 4). Trends in AE occurrence were evident by week 1 and percentage of AEs were similar across weeks 3, 4, and 6. The overall concordance rate between change from baseline in the modified PANSS score and change from baseline in the total PANSS score was 93.0% (80 of 86 treatment groups) at week 4 and 97.7% (84 of 86 treatment groups) at week 6. Shortening the trial duration to 4 weeks increased the required sample size to 502 participants. Using the modified PANSS as the end point, the sample size for a 4-week trial was 402 participants and 296 participants for a 6-week trial. Findings from this analysis suggest that there is the potential to streamline the design of schizophrenia drug clinical trials. Trial sponsors may consider incorporating these strategies and are encouraged to consult with the FDA early in the drug development process.

Reporting standards for endovascular aortic repair of aneurysms involving the renal-mesenteric arteries

Endovascular aortic aneurysm repair of complex aortic aneurysms requires incorporation of side branches using specially designed aortic stent grafts with fenestrations, directional branches, or parallel stent grafts. These techniques have been increasingly used and reported in the literature. The purpose of this document is to clarify and to update terminology, classification systems, measurement techniques, and end point definitions that are recommended for reports dealing with endovascular repair of complex abdominal and thoracoabdominal aortic aneurysms involving the renal and mesenteric arteries.

Infective Endocarditis After Transcatheter Aortic Valve Replacement

BackgroundInfective endocarditis may affect patients after transcatheter aortic valve replacement (TAVR). ObjectivesThe purpose of this study was to provide detailed information on incidence rates, types of microorganisms, and outcomes of infective endocarditis after TAVR. MethodsBetween February 2011 and July 2018, consecutive patients from the SwissTAVI Registry were eligible. Infective endocarditis was classified into early (peri-procedural [<100 days] and delayed-early [100 days to 1 year]) and late (>1 year) endocarditis. Clinical events were adjudicated according to the Valve Academic Research Consortium-2 endpoint definitions. ResultsDuring the observational period, 7,203 patients underwent TAVR at 15 hospitals in Switzerland. During follow-up of 14,832 patient-years, endocarditis occurred in 149 patients. The incidence for peri-procedural, delayed-early, and late endocarditis after TAVR was 2.59, 0.71, and 0.40 events per 100 person-years, respectively. Among patients with early endocarditis, Enterococcus species were the most frequently isolated microorganisms (30.1%). Among those with peri-procedural endocarditis, 47.9% of patients had a pathogen that was not susceptible to the peri-procedural antibiotic prophylaxis. Younger age (subhazard ratio [SHR]: 0.969; 95% confidence interval [CI]: 0.944 to 0.994), male sex (SHR: 1.989; 95% CI: 1.403 to 2.818), lack of pre-dilatation (SHR: 1.485; 95% CI: 1.065 to 2.069), and treatment in a catheterization laboratory as opposed to hybrid operating room (SHR: 1.648; 95% CI: 1.187 to 2.287) were independently associated with endocarditis. In a case-control matched analysis, patients with endocarditis were at increased risk of mortality (hazard ratio: 6.55; 95% CI: 4.44 to 9.67) and stroke (hazard ratio: 4.03; 95% CI: 1.54 to 10.52). ConclusionsInfective endocarditis after TAVR most frequently occurs during the early period, is commonly caused by Enterococcus species, and results in considerable risks of mortality and stroke. (NCT01368250)

Comparative Effectiveness of Calcimimetic Agents for Secondary Hyperparathyroidism in Adults: A Systematic Review and Network Meta-analysis

Comparative benefits and harms of calcimimetic agents used for the treatment of secondary hyperparathyroidism have not been well characterized. We sought to compare the effectiveness of 3 calcimimetic agents using published data. Systematic review of randomized controlled trials and network meta-analysis. Adults with chronic kidney disease enrolled in a clinical trial of a calcimetic agent. MEDLINE, EMBASE, CENTRAL (from February 7, 2013, to November 21, 2019), and a published meta-analysis. Two reviewers independently extracted the study data, assessed risk of bias, and rated evidence certainty using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Frequentist network meta-analysis was conducted. The primary review outcomes were achievement of a target reduction in serum parathyroid hormone (PTH) levels and hypocalcemia. Additional outcomes were nausea, vomiting, serious adverse events, all-cause mortality, cardiovascular mortality, heart failure, and fracture. 36 trials (11,247 participants) were included. All except 4 trials involved dialysis patients. Median follow-up was 26 weeks (range, 1 week to 21.2 months). Compared with placebo, calcimimetic agents had higher odds of achieving target PTH levels with high or moderate certainty. Etelcalcetide had the highest odds of achieving a PTH target compared with evocalcet (OR, 4.93; 95% CI, 1.33-18.2) and cinacalcet (OR, 2.78; 95% CI, 1.19-6.67). Etelcalcetide appeared to cause more hypocalcemia than cinacalcet and evocalcet. Cinacalcet and to a lesser extent etelcalcetide appeared to cause more nausea than placebo. Differences in risk for mortality, cardiovascular end points, or fractures across calcimimetic agents could not be discerned with sufficient certainty. Lack of longer-term data; heterogeneous end point definitions. Evidence of the benefits of calcimimetic therapy is limited to short-term assessment of a putative surrogate outcome (serum PTH). Although etelcalcetide was associated with the largest reduction in PTH levels, side-effect profiles differed across the 3 calcimimetic agents, making it not possible to identify 1 preferred agent.

Repeated gamma knife radiosurgery enables longer tumor control in cases of highly-recurrent intracranial ependymoma.

Stereotactic radiosurgery (SRS) is a potential re-irradiation treatment for recurrent intracranial ependymoma after prior radiation therapy. The purpose of this study was to examine the efficacy and safety of repeated SRS in the treatment of recurrent intracranial ependymomas. This is a retrospective study of consecutive patients with residual or recurrent intracranial ependymomas who were treated with SRS between 1993 and 2018. Tumor progression was defined as a ≥ 10% increase in tumor volume. Tumor regression was defined as a ≥ 10% reduction in tumor volume. A tumor that remained within 10% of its original volume was defined as stable. Tumor control comprised tumor regression and stability. Time-dependent analyses were performed using two treatment failure endpoint definitions: (1) evidence of local tumor progression or distant metastasis (single SRS analysis), and (2) lack of tumor response to SRS (repeated SRS analysis). These analyses were adjusted for the competing risk of death. The study comprised 37 patients (65 intracranial ependymomas) who underwent multiple SRS sessions (range: 1-7). Median age was 10.2years (range: 0.8-53.8years), and median tumor volume was 1.5mL (range: 0.01-22.5mL). The median radiation dose was 13.3Gy (range: 7.9-22.0Gy) at a median isodose line of 57% (range: 50-90%). Overall tumor control rates in the single SRS analysis adjusting for the competing risk of death were 53.6%, 30.5%, and 23.6% at 1, 3, and 5years, respectively. Overall tumor control rates in the repeated SRS analysis adjusting for the competing risk of death were 70.6%, 50.4%, and 43.1% at 1, 3, and 5years, respectively. Prior gross total resection was the only independent predictor of overall tumor control after SRS (aHR = 25.62 (1.55-422.1), p = 0.02). Repeated GKRS appeared to be an effective treatment strategy for recurrent or residual intracranial ependymomas, with acceptable complication rates.

Statistical aspects in adjuvant and neoadjuvant trials for gastrointestinal cancer in 2020: focus on time-to-event endpoints.

Clinical-trial design, analysis, and interpretation entails the use of efficient and reliable endpoints. Statistical issues related to endpoints warrant continued attention, as they may have a substantial impact on the conduct of clinical trials and on interpretation of their results. We review concepts and discuss recent developments related to the use of time-to-event endpoints in studies on adjuvant and neoadjuvant therapy for colon, pancreatic, and gastric adenocarcinomas. The definition of endpoints has varied to a considerable extent in these settings. Although these variations are relevant in interpreting results from individual trials, they probably have a small impact when considered in aggregate. In terms of surrogacy, most published reports so far have used aggregated data. A few studies based on the preferred method of a metaanalysis of individual-patient data have shown that disease-free survival (DFS) is a surrogate for overall survival in the adjuvant therapy of stage III colon cancer and in gastric cancer, whereas DFS with a landmark of six months is a surrogate for overall survival in the neoadjuvant therapy of adenocarcinoma of the esophagus, gastroesophageal junction, or stomach. Testing novel agents in gastrointestinal cancer requires continued attention to statistical issues related to endpoints.

Monotherapy with a P2Y12 inhibitor or aspirin for secondary prevention in patients with established atherosclerosis: a systematic review and meta-analysis

Antiplatelet therapy is recommended among patients with established atherosclerosis. We compared monotherapy with a P2Y12 inhibitor versus aspirin for secondary prevention. In this systematic review and meta-analysis, all randomised trials comparing P2Y12 inhibitor with aspirin monotherapy for secondary prevention in patients with cerebrovascular, coronary, or peripheral artery disease were evaluated for inclusion. On Dec 18, 2019, we searched PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials. Additionally, we reviewed references from identified articles and searched abstracts from 2017 to 2019 presented at relevant scientific meetings. Data about year of publication, inclusion and exclusion criteria, sample size, baseline patients' features including the baseline condition determining study inclusion (ie, cerebrovascular, coronary, or peripheral artery disease), P2Y12 inhibitor type and dosage, aspirin dosage, endpoint definitions, effect estimates, follow-up duration, and percentage of patients lost to follow-up were collected. Odds ratios (ORs) and 95% CIs were used as metric of choice for treatment effects with random-effects models. Co-primary endpoints were myocardial infarction and stroke. Key secondary endpoints were all-cause death and vascular death. Heterogeneity was assessed with the I2 index. This study is registered with PROSPERO (CRD42018115037). A total of nine randomised trials were identified and included in this study, and 42 108 patients randomly allocated to a P2Y12 inhibitor (n=21 043) or aspirin (n=21 065) were included in our analyses. Patients who received a P2Y12 inhibitor had a borderline reduction for the risk of myocardial infarction compared with those who received aspirin (OR 0·81 [95% CI 0·66-0·99]; I2=10·9%). Risks of stroke (OR 0·93 [0·82-1·06]; I2=34·5%), all-cause death (OR 0·98 [0·89-1·08]; I2=0%), and vascular death (OR 0·97 [0·86-1·09]; I2=0%) did not differ between patients who received a P2Y12 inhibitor and those who received aspirin. Similarly, the risk of major bleeding (OR 0·90 [0·74-1·10]; I2=3·9%) did not differ between patients who received a P2Y12 inhibitor and those who received aspirin. The number needed to treat to prevent one myocardial infarction with P2Y12 inhibitor monotherapy was 244 patients. Findings were consistent regardless of the type of P2Y12 inhibitor used. Compared with aspirin monotherapy, P2Y12 inhibitor monotherapy is associated with a risk reduction for myocardial infarction and a comparable risk of stroke in the setting of secondary prevention. The benefit of P2Y12 inhibitor monotherapy is of debatable clinical relevance, in view of the high number needed to treat to prevent a myocardial infarction and the absence of any effect on all-cause and vascular mortality. Italian Ministry of Education.

Recovery in Psychosis: Perspectives of Clients with First Episode Psychosis

Recovery from psychosis relates to connectedness, hope for the future, identity, meaning in life and empowerment. The process of recovery is often described as gradual and non-linear, with many stages and turning points, and without a definitive end point. This qualitative study aims to understand what recovery means to clients, to better understand their unique recovery process and what helps in recovery among clients with lived experience of first episode psychosis (FEP) in a developed Asian setting. The study design and interview guide development included inputs from persons with psychosis, following which 7 focus group discussions were conducted with 40 FEP clients of a tertiary care psychiatric institute. Thematic qualitative analysis identified three themes: 1) meaning of recovery (where participants expressed their views on what recovery meant to them); 2) recovery as a journey (due to the constant ups and downs in the long process of recovery, it was often articulated as a "journey"); and 3) facilitators of recovery (related to resources, practices and experiences that supported their recovery). The emergent themes provide an understanding of the meaning of recovery to persons with FEP, their experiences as they proceed with their recovery journey and factors they found helpful. The importance of acceptance of the condition and the personal role the individual plays in his or her own recovery was evident in the narratives of the participants. The study suggests a need to incorporate recovery-relevant approaches right from the first episode of psychosis.

Complete and transparent reporting of primary end points of randomized trials in the dermatology literature: A comparison of registered and published primary end points

Appropriate primary end points in randomized controlled trials (RCTs) improve the quality of the measurement and enable comparison of the findings with those of other trials. To assess the quality of reporting primary end points in RCTs recently published in dermatology journals. We identified 134 primary reports of RCTs among original articles in 4 dermatology journals published from January 2016 to December 2018. Details were extracted from articles, supplements, and trial registries. A multivariable logistic regression analysis was conducted to identify factors associated with adequate primary end point reporting. Adequate primary end point reporting was conducted in 76 of 134 RCTs (56.7%). Nine missed the definition of primary end points, and 13 did not define the timing of primary end points in the publications. Among 113 RCTs reporting primary end points explicitly in the articles, 16 showed discrepancies between registration and publication, and 21 were not able to valuate prespecification of primary end points. Multicenter studies and sponsor-initiated trials were significantly associated with adequate reporting quality after adjusting for covariates. Prespecification was evaluated based on a comparison of the article and registry. The quality of primary end point reporting, particularly in prespecification, has remained unsatisfactory in the recent dermatology literature.