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Rationale: Severe symptomatic aortic stenosis (SSAS) is the most common acquired valvular heart disease in the western world, and its prevalence is strongly linked to the phenomenon of population ageing. After symptom onset, patients with SSAS, if untreated, show very poor prognoses, unavoidably reaching complete disability status with a significant reduction in survival. Although aortic valve replacement (AVR) is the definitive therapy for this kind of patients, a new, less-invasive alternative like transcatheter aortic valve implantation (TAVI) has been considered, at least for a large proportion of patients with very high or prohibitive operative risks. OBSERVANT represents the first observational multicenter perspective study on the comparative effectiveness of TAVI, AVR, and medical therapy in the Italian population with SSAS., Materials and Methods: In the participating hospitals, to define the patient risk profile for each patient with SSAS, data on demographic characteristics, health status prior to intervention and presence of comorbidities will be collected. Moreover, complete information on the type of intervention will be gathered. Mortality within 30 days from intervention is the primary adverse outcome. Secondary outcomes include mortality within 12 and 24 months and the incidence of in-hospital major adverse cardiac and cerebrovascular events. Clinical monitoring procedures will allow assessment of the reliability and completeness of the database and help maintain constant quality control. To compare the effectiveness of AVR, TAVI, and medical treatment in terms of medium- and long-term outcomes, accounting for possible differences in patient case-mix among the three treatment groups, risk adjustment techniques will be applied., Expected Results: Short-, medium-, and long-term outcome in patients undergoing one of the three SSAS treatments; use, appropriateness, and economic and organizational impact of TAVI and AVR procedures; specific "indication criteria" to guarantee appropriate patient selection for AVR or TAVI; new pre-procedure risk score, specific for the elderly Italian population; guidelines on TAVI procedure coding and a system of administrative follow-up to be proposed to the regional health systems for managing the use of the AVR or TAVI procedures., Conclusions: The complete knowledge base derived from this study will be directly transferable to professionals and policy makers, giving them evidence-based results for use in their decision-making process.

Introduction: Recent phase III studies in advanced non-small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology., Patients and Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m2 plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m2 plus oxaliplatin 120 mg/m2 (n = 41); both regimens were administered every 21 days. The primary endpoint of both trials was response rate. Treatment arms were pooled, and Cox models with main effects for squamous histology were used to assess overall survival and progression-free survival. Cofactor adjustments incorporated terms for performance status, disease stage, and sex., Results: More than three quarters of enrolled patients had a nonsquamous histology. Mean age was 59.9 years for patients with nonsquamous histology and 63.7 years for patients with squamous histology. Response rates were 30% for patients with nonsquamous histology and 17.2% for patients with squamous histology. Overall survival was 10.5 months for patients with nonsquamous histology and 9.8 months for patients with squamous histology (hazard ratio [HR], 0.95; 95% CI, 0.52-1.74). Progression-free survival was 5.6 months for patients with nonsquamous histology and 4.7 months for patients with squamous histology (HR, 0.72; 95% CI, 0.43-1.19)., Conclusion: In patients treated with pemetrexed/ platinum doublets, nonsquamous histology was associated with better outcomes. The benefit of pemetrexed treatment among patients with nonsquamous histology is consistent with the results reported from previous studies.

Introduction: These analyses examine survival from the start of renal replacement therapy (RRT), based on the total incident UK RRT population reported to the UK Renal Registry, including the 19% who started on PD and the 5% who received a pre-emptive transplant. Survival of prevalent patients and changes in survival between 1997 and 2007 are also reported., Methods: Survival was calculated for both incident and prevalent patients on RRT and compared between the UK countries after adjustment for age. Survival of incident patients (starting RRT during 2007) was calculated both from the start of RRT and amongst the cohort who survived at least 90 days after RRT, and both with and without censoring at transplantation. Both the Kaplan-Meier and Cox adjusted models were used to calculate survival. Causes of death were analysed for both groups. Relative risk of death was calculated compared with the general UK population., Results: The 2007 unadjusted 1 year after 90 day survival for patients starting RRT was 86.2%. In incident 18-64 year olds the unadjusted 1 year survival had risen from 85.9% in 1997 to 92.4% in 2007 and for those aged >65 it had risen from 63.8% to 74.9%. The age-adjusted survival (adjusted to age 60) of prevalent dialysis patients rose from 85% in 2000 to 89% in 2007. Diabetic prevalent patient survival rose from 76.5% in 2000 to 83.0% in 2007. The age-standardised mortality ratio for prevalent RRT patients compared with the general population was 28.6 at age 30 years (and was lower than in the 1998-2001 cohort in all age groups up to 45-49) and 4.6 at age 80 years. In the prevalent RRT dialysis population, cardiovascular disease accounted for 29% of deaths, infection 17% and treatment withdrawal 14%. Of deaths, 26% were recorded as uncertain. Treatment withdrawal was a more frequent cause of death in patients aged >65 at start than in younger patients. The median life years remaining for a 25-29 year old on RRT was 20 years and 5 years for a 70 year old., Conclusions: Incident 2007 and prevalent 2008 patient survival on RRT in all the UK countries for all age ranges and also for patients with diabetes continued to improve. The relative risk of death on RRT compared with the general population has fallen since 2001. Death rates on dialysis in the UK remained lower than when compared with a similar aged population on dialysis in the USA., ((c) 2010 S. Karger AG, Basel.)

Background: There is a shortage of randomized controlled trials (RCTs) on which to base guidelines in liver surgery. The feasibility of conducting an adequately powered RCT in liver surgery using the dichotomous endpoints surgery-related mortality or morbidity was examined., Methods: Articles published between January 2002 and November 2007 with mortality or morbidity after liver surgery as primary endpoint were retrieved. Sample size calculations for a RCT aiming to show a relative reduction of these endpoints by 33, 50 or 66 per cent were performed., Results: The mean operative mortality rate was 1.0 per cent and the total morbidity rate 28.9 per cent; mean rates of bile leakage and postresectional liver failure were 4.4 and 2.6 per cent respectively. The smallest numbers of patients needed in each arm of a RCT aiming to show a 33 per cent relative reduction were 15 614 for operative mortality, 412 for total morbidity, 3446 for bile leakage and 5924 for postresectional liver failure., Conclusion: The feasibility of conducting an adequately powered RCT in liver surgery using outcomes such as mortality or specific complications seems low. Conclusions of underpowered RCTs should be interpreted with caution. A liver surgery-specific composite endpoint may be a useful and clinically relevant solution to pursue., ((c) 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Introduction: We performed a study to determine whether an enrollment sequence effect noted in the PROWESS (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis) trial exists in the ADDRESS (Administration of Drotrecogin Alfa [Activated] [DrotAA] in Early Stage Severe Sepsis) trial., Methods: We evaluated prospectively defined subgroups from two large phase 3 clinical trials: ADDRESS, which included 516 sites in 34 countries, and PROWESS, which included 164 sites in 11 countries. ADDRESS consisted of patients with severe sepsis at low risk of death not indicated for treatment with DrotAA. PROWESS consisted of patients with severe sepsis with one or more organ dysfunctions. DrotAA (24 microg/kg per hour) or placebo was infused for 96 hours., Results: In ADDRESS and PROWESS, there was a statistically significant interaction between the DrotAA treatment effect and the sequence in which patients were enrolled. In both trials, higher mortality was associated with DrotAA use in the subgroup of patients enrolled first at study sites. Compared with placebo, PROWESS mortality was lower with DrotAA treatment for the second and subsequent patients enrolled, whereas in ADDRESS, mortality remained higher for the second patient enrolled but thereafter was lower for DrotAA-treated patients. Comparison of patients enrolled first with subsequent patients enrolled indicated that the characteristics of patients changed. Subsequently enrolled patients were treated earlier, were less likely to suffer nonserious bleeds (ADDRESS), and experienced fewer protocol violations (PROWESS)., Conclusions: Analyses suggest that an enrollment sequence effect was present in the ADDRESS and PROWESS trials. Analysis of this effect on outcomes suggests that it is most apparent in patients at lower risk of death. In PROWESS, this effect appeared to be associated with a reduction of the DrotAA treatment effect for the first patients enrolled at each site. In ADDRESS, this effect may have contributed to early termination of the study. The finding of an enrollment sequence effect in two separate trials suggests that trial designs, site selection and training, data collection and monitoring, and statistical analysis plans may need to be adjusted for these potentially confounding events., Trial Registration: ADDRESS trial registration number: NCT00568737. PROWESS was completed before trial registration was required.