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OBJECTIVEIn the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio [HR] 0.62 [95% CI 0.49, 0.77]). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin. RESEARCH DESIGN AND METHODSEffects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed. RESULTSChanges in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA 1c . In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death. CONCLUSIONSIn this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, was the first glucose-lowering agent to demonstrate a reduction in cardiovascular (CV) death in patients with type 2 diabetes and high CV risk (1). In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, over a median observation time of 3.1 years, treatment

Prognostic classification schemes have often been used in medical applications, but rarely subjected to a rigorous examination of their adequacy. For survival data, the statistical methodology to assess such schemes consists mainly of a range of ad hoc approaches, and there is an alarming lack of commonly accepted standards in this field. We review these methods and develop measures of inaccuracy which may be calculated in a validation study in order to assess the usefulness of estimated patient‐specific survival probabilities associated with a prognostic classification scheme. These measures are meaningful even when the estimated probabilities are misspecified, and asymptotically they are not affected by random censorship. In addition, they can be used to derive R2‐type measures of explained residual variation. A breast cancer study will serve for illustration throughout the paper. Copyright © 1999 John Wiley & Sons, Ltd.

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Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD).Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] ‫؍‬ 1.21, P ‫؍‬ .47, and HR ‫؍‬ 0.68, P ‫؍‬ .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR ‫؍‬ 0.84, P ‫؍‬ .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity. (Blood. 2011; 117(23):6375-6382) IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used worldwide as a curative therapy for malignant and nonmalignant hematologic disorders. Chronic graft-versushost disease (cGVHD) is the leading cause of nontransplantation mortality and morbidity after allogeneic HSCT. 1-3 cGVHD is a multiorgan disease resembling autoimmune disorders, such as scleroderma or systemic lupus. 4,5 Its incidence and prevalence are rising because of transplantation practices known to be associated with increased risk of cGVHD. 4,6 Indeed, older patients now undergo HSCT, and more transplantations are being performed from unrelated donors and/or with peripheral blood stem cells instead of bone marrow. Furthermore, the reduced-intensity conditioning (RIC) regimens developed during recent years have also led to higher numbers of transplantations performed worldwide. 7,8 However, although the acute GVHD (aGVHD) rate appears lower after RIC, the incidence of cGVHD seems to be unaffected. 9 Altogether, cGVHD thus remains the most challenging complication after allogeneic HSCT. 10 The main risk factor for developing cGVHD is the previous occurrence of aGVHD. 11 Thus, transplantation physicians have focused on decreasing the rate of aGVHD to lower nonrelapse mortality (NRM) associated with both aGVHD and cGVHD. However, although calcineurin inhibitors (cyclosporine or tacrolimus) in association with methotrexate have proven to decrease the aGVHD rate in randomized studies and although new regimens, such as the association of rapamycin with tacrolimus, seem to l...

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BackgroundRecent randomized controlled trials comparing neoadjuvant chemoradiation plus surgery or perioperative chemotherapy plus surgery with surgery alone showed significant survival benefits for combined modality treatment of patients with localized esophageal adenocarcinoma. However, head-to-head comparisons of neoadjuvant chemoradiation and perioperative chemotherapy applying contemporary treatment protocols are lacking. The present trial was initiated to obtain valid information whether neoadjuvant chemoradiation or perioperative chemotherapy yields better survival in the treatment of localized esophageal adenocarcinoma.Methods/designThe ESOPEC trial is an investigator-initiated multicenter prospective randomized controlled two-arm trial, comparing the efficacy of neoadjuvant chemoradiation (CROSS protocol: 41.4Gy plus carboplatin/paclitaxel) followed by surgery versus perioperative chemotherapy and surgery (FLOT protocol: 5-FU/leucovorin/oxaliplatin/docetaxel) for the curative treatment of localized esophageal adenocarcinoma. Patients with cT1cN + cM0 and cT2-4acNxcM0 esophageal and junctional adenocarcinoma are eligible. The trial aims to include 438 participants who are centrally randomized to one of the two treatment groups in a 1:1 ratio stratified by N-stage and study site. The primary endpoint of the trial is overall survival assessed with a minimum follow-up of 36 months. Secondary objectives are progression-free survival, recurrence-free survival, site of failure, postoperative morbidity and mortality, duration of hospitalization as well as quality of life.DiscussionThe ESOPEC trial compares perioperative chemotherapy according to the FLOT protocol to neoadjuvant chemoradiation according to the CROSS protocol in multimodal treatment of non-metastasized recectable adenocarcinoma of the esophagus and the gastroesophageal junction. The goal of the trial is identify the superior protocol with regard to patient survival, treatment morbidity and quality of life. Trial registrationNCT02509286 (July 22, 2015)Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2564-y) contains supplementary material, which is available to authorized users.

The use of TAVR increased markedly in Germany between 2007 and 2013; the concomitant reduction in the use of surgical aortic-valve replacement was moderate. Patients undergoing TAVR were older and at higher procedural risk than those undergoing surgical aortic-valve replacement. In-hospital mortality decreased in both groups but to a greater extent among patients undergoing TAVR. (Funded by the Heart Center, Freiburg University.).