Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications

OBJECTIVE: To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN: Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING: Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES: 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS: Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS: Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Postmortem magnetic resonance imaging of the heart ex situ: development of technical protocols.

Postmortem MRI (PMMR) examinations are seldom performed in legal medicine due to long examination times, unfamiliarity with the technique, and high costs. Furthermore, it is difficult to obtain access to an MRI device used for patients in clinical settings to image an entire human body. An alternative is available: ex situ organ examination. To our knowledge, there is no standardized protocol that includes ex situ organ preparation and scanning parameters for postmortem MRI. Thus, our objective was to develop a standard procedure for ex situ heart PMMR examinations. We also tested the oily contrast agent Angiofil® commonly used for PMCT angiography, for its applicability in MRI. We worked with a 3 Tesla MRI device and 32-channel head coils. Twelve porcine hearts were used to test different materials to find the best way to prepare and place organs in the device and to test scanning parameters. For coronary MR angiography, we tested different mixtures of Angiofil® and different injection materials. In a second step, 17 human hearts were examined to test the procedure and its applicability to human organs. We established two standardized protocols: one for preparation of the heart and another for scanning parameters based on experience in clinical practice. The established protocols enabled a standardized technical procedure with comparable radiological images, allowing for easy radiological reading. The performance of coronary MR angiography enabled detailed coronary assessment and revealed the utility of Angiofil® as a contrast agent for PMMR. Our simple, reproducible method for performing heart examinations ex situ yields high quality images and visualization of the coronary arteries.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Référentiel de pratiques professionnelles: soins et surveillance des accès veineux centraux de l'adulte pour la nutrition parentérale [Formative assessment in clinical nutrition: Care management of parenteral nutrition central venous access]

Les voies veineuses centrales (VVC) sont essentielles pour l'administration de la nutrition parentérale. Le risque de complications est dépendant de la qualité des soins apportés à la VVC qui influence de ce fait la qualité de vie des patients et le coût des soins. Beaucoup de complications des VVC, infectieuses ou non, peuvent être prévenues par l'existence de protocoles de soins appropriés et standardisés. L'information sur les soins des VVC et les éventuelles complications est essentielle pour le dépistage et le traitement précoce de ces complications ; elle doit faire l'objet de protocoles partagés entre les patients et les soignants. Cet article décrit une évaluation des pratiques professionnelles sous la forme d'un audit clinique destiné à améliorer la qualité de soins des patients en nutrition parentérale porteurs de VVC. Central venous access devices (CVAD) are essential for the administration of parenteral nutrition. The quality of the care of CVAD influences the risk of complications and so the quality of life of the patients and the costs of care. Numerous infectious or non-infectious complications of CVAD can be prevented by appropriate, standardized protocols of care. Information about the care of CVAD and complications is essential for the early recognition and treatment of complications and should be shared between patients and caregivers. This article describes an audit for CAVD care that can be used to improve quality of care in a professional practice evaluation program.

Transcatheter stent-valve implantation in a stenotic pulmonary conduit via a sub-xyphoidian access

Patients who develop a severe stenosis in biological pulmonary conduits previously implanted for pulmonary outflow trunk reconstructions are treated either by surgical re-replacement, or by transcatheter stent-valve implantation through a femoral vein access. A catheter-based sub-xyphoidian access through the right ventricle for stent-valve positioning in a pulmonary conduit has rarely been proposed. We describe the case of a 20-year-old man who underwent a pulmonary trunk reconstruction for a congenital pulmonary valve dysplasia and a few years later developed a stenosis in the pulmonary conduit. He was successfully treated with a 23 mm Edwards Sapien stent-valve implantation in pulmonary position, through an unusual right ventricular, sub-xyphoidian access and without contrast medium injections and pleura opening.

Engorgement des centres d'urgences: une raison légitime de refuser l'accès aux patients non urgents [Emergency department overcrowding: a legitimate reason to refuse access to urgent care for non-urgent patients?].

Non-urgent cases represent 30-40% of all ED consults; they contribute to overcrowding of emergency departments (ED), which could be reduced if they were denied emergency care. However, no triage instrument has demonstrated a high enough degree of accuracy to safely rule out serious medical conditions: patients suffering from life-threatening emergencies have been inappropriately denied care. Insurance companies have instituted financial penalties to discourage the use of ED as a source of non-urgent care, but this practice mainly restricts access for the underprivileged. More recent data suggest that in fact most patients consult for appropriate urgent reasons, or have no alternate access to urgent care. The safe reduction of overcrowding requires a reform of the healthcare system based on patients' needs rather than access barriers.

Access to information in Switzerland : From secrecy to transparency

Access to information legislations are now present in over 50 countries world-wide. Lagging behind some of its own Cantons, the Swiss Federal government was until recently one of the few hold outs in Europe. But, in December 2004, the Confederation voted the 'Loi sur la Transparence de l'administration' or Law on Transparency (LTrans) a Law that came into effect in July 2006. This paper presents an overview of the new Law and underlines the main institutional challenges to its introduction in Switzerland.

trEST, trGEN and Hits: access to databases of predicted protein sequences.

High throughput genome (HTG) and expressed sequence tag (EST) sequences are currently the most abundant nucleotide sequence classes in the public database. The large volume, high degree of fragmentation and lack of gene structure annotations prevent efficient and effective searches of HTG and EST data for protein sequence homologies by standard search methods. Here, we briefly describe three newly developed resources that should make discovery of interesting genes in these sequence classes easier in the future, especially to biologists not having access to a powerful local bioinformatics environment. trEST and trGEN are regularly regenerated databases of hypothetical protein sequences predicted from EST and HTG sequences, respectively. Hits is a web-based data retrieval and analysis system providing access to precomputed matches between protein sequences (including sequences from trEST and trGEN) and patterns and profiles from Prosite and Pfam. The three resources can be accessed via the Hits home page (http://hits. isb-sib.ch).

Access to specialized pediatric cancer care in Switzerland.

BACKGROUND: Specialized pediatric cancer centers (PCCs) are thought to be essential to obtain state-of-the-art care for children and adolescents. We determined the proportion of childhood cancer patients not treated in a PCC, and described their characteristics and place of treatment. PROCEDURE: The Swiss Childhood Cancer Registry (SCCR) registers all children treated in Swiss PCCs. The regional cancer registries (covering 14/26 cantons) register all cancer patients of a region. The children of the SCCR with data from 7 regions (11 cantons) were compared, using specialized software for record linkage. All children <16 years of age at diagnosis with primary malignant tumors, diagnosed between 1990 and 2004, and living in one of these regions were included in the analysis. RESULTS: 22.1% (238/1,077) of patients recorded in regional registries were not registered in the SCCR. Of these, 15.7% (169/1,077) had never been in a PCC while 6.4% (69/1,077) had been in a PCC but were not registered in the SCCR, due to incomplete data flow. In all diagnostic groups and in all age groups, a certain proportion of children was treated outside a PCC, but this proportion was largest in children suffering from malignant bone tumors/soft tissue sarcomas and from malignant epithelial neoplasms, and in older children. The proportion of patients treated in a PCC increased over the study period (P < 0.0001). CONCLUSIONS: One in six childhood cancer patients in Switzerland was not treated in a PCC. Whether these patients have different treatment outcomes remained unclear.