Svenja Schüler

Development of a new Emergency Medicine Spinal Immobilization Protocol for trauma patients and a test of applicability by German emergency care providers

BackgroundIn order to match the challenges of quickly recognizing and treating any life-threatening injuries, the ABCDE principles were established for the assessment and treatment of trauma patients. The high priority of spine protection is emphasized by the fact that immobilization of the cervical spine is performed at the very first step in the ABCDE principles. Immobilization is typically performed to prevent or minimize secondary damage to the spinal cord if instability of the spinal column is suspected. Due to increasing reports about disadvantages of spinal immobilization, the indications for performing spinal immobilization must be refined.The aim of this study was (i) to develop a protocol that supports decision-making for spinal immobilization in adult trauma patients and (ii) to carry out the first applicability test by emergency medical personnel.MethodsA structured literature search considering the literature from 1980 to 2014 was performed. Based on this literature and on the current guidelines, a new protocol that supports on scene decision-making for spinal immobilization has been developed. Parameters found in the literature concerning mechanisms and factors increasing the likelihood of spinal injury have been included in the new protocol. In order to test the applicability of the new protocol two surveys were performed on German emergency care providers by means of a questionnaire focused on correct decision-making if applying the protocol.ResultsBased on the current literature and guidelines, the Emergency Medicine Spinal Immobilization Protocol (E.M.S. IMMO Protocol) for adult trauma patients was developed. Following a fist applicability test involving 21 participants, the first version of the E.M.S. IMMO Protocol has to be graphically re-organized. A second applicability test comprised 50 participants with the current version of the protocol confirmed good applicability. Questions regarding immobilization of trauma patients could be answered properly using the E.M.S. IMMO Protocol.DiscussionCurrent literature increasingly reports of disadvantages that may be associated with immobilization. Based on the requirements of the current guidelines, a new protocol that supports decision-making for indications for out-of-hospital spinal immobilization has been developed in this study. In contrast to established protocols, the new protocol offers different options for immobilization as well as a decicion-support.ConclusionsThe E.M.S. IMMO protocol provides a decision-support tool for indications for spinal immobilization in adult trauma patients that permits variable decision-making depending on the current condition of the trauma patient and the pattern of injuries for immobilization in general and for immobilization method in particular.

Easily applicable multiple testing procedures to improve the interpretation of clinical trials with composite endpoints

BACKGROUND Cardiology trials often consider composite endpoints as primary efficacy outcomes thereby combining several time-to-event variables in a single time-to-first-event measure. The main motivation to use a composite endpoint is to increase the number of expected events thereby reducing the required sample size. However, interpretation may be difficult as the effect observed for the composite endpoint does not necessarily reflect the effects for the single components. To improve interpretation, it is therefore a current standard to analyze the individual components in a descriptive way. However, a descriptive analysis does not allow a statistical proof of concept. Therefore the gain in information is limited. METHODS This paper systematically explores multiple testing procedures aimed at improving the interpretation of composite endpoints by confirmatory tests of the components. A simulation study demonstrates, on the basis of a real cardiology clinical trial example, the benefit of these easily applicable multiple testing procedures. RESULTS By applying adequate multiple testing strategies to assess the components of a composite endpoint there is a high chance to get additional confirmatory evidence on the components without the need to increase sample size. With a moderate increase in sample size, a gain in evidence can often also be ensured with a predefined power. CONCLUSION The interpretation of composite endpoints can be improved by applying multiple testing procedures that assess the components. The methods discussed here are easy to apply and provide a substantial benefit for clinical interpretation of study results.

Adaptive Designs for Two Candidate Primary Time-to-Event Endpoints

ABSTRACT In clinical trials, the choice of an adequate primary endpoint is often difficult. Besides its clinical relevance, the endpoint must be measurable within reasonable time and must allow differentiating between the treatments. Often, the most relevant endpoint is ‘’time-to-death,” but if the overall survival prognosis is good, only a few deaths are observed during the study duration. A possible solution is to use surrogate endpoints instead. However, various examples from the literature demonstrate that surrogates do not always perform as intended. Sometimes, the surrogate effect is smaller than for the original endpoint, or the latter shows a higher effect than anticipated so using the surrogate is not reasonable. In this work, different adaptive design strategies for two candidate endpoints are proposed to solve these problems. The idea is to base the efficacy proof on the significance of at least one endpoint. At an interim analysis, both candidates are evaluated. If it is not possible to stop the study early, the sample size is recalculated based on the more promising endpoint. The new methods are illustrated by a clinical study example and compared in terms of power and sample size using Monte Carlo simulations. The software code is provided as supplementary material.

Choice of futility boundaries for group sequential designs with two endpoints

BackgroundIn clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called ‘group sequential designs’ are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics.MethodsIn this work, we propose a general method to construct ‘optimal’ futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations.ResultsBy construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study ‘wrongly’. Our results clearly demonstrate the benefit of using such ‘optimal’ futility boundaries, especially compared to futility boundaries commonly applied in practice.ConclusionsAs the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the performance of these boundaries according to the criteria proposed in here.

Changes in Cognitive Function after Left Atrial Appendage Occlusion

Background: Cognitive dysfunction is a frequent phenomenon after surgical and cardiovascular interventions. No data on cognitive function after left atrial appendage occlusion (LAAO) are available so far. The aim of the present study was to evaluate the cognitive function after LAAO compared to before LAAO. Methods and findings: Patients who underwent LAAO for treatment of atrial fibrillation at the Heidelberg Department of Internal Medicine III were eligible for this observational, explorative, single-center, non-randomized cohort study, between July 2013 and January 2016. Neurological examination and neuropsychological assessments were conducted one day before LAAO and one month after LAAO, using a comprehensive neuropsychological test battery that included several cognitive domains including executive function, verbal fluency, verbal and non-verbal memory. Paired t-tests and correlation analyses were applied to compare test results pre- and post-intervention. In addition, we descriptively analyzed the number of relevant changes (± 1 standard deviation) over all cognitive domains for each patient. 20 patients completed the study. Mean age was 72.6 ± 6.8 years and 15 (75%) were male. There were no significant changes in any of the tested cognitive domains in group statistics. Descriptive single case analysis showed more deteriorations than improvements by one standard deviation over all cognitive domains in three patients, while in 11 patients the number of positive changes exceeded the number of negative changes. Conclusion: LAAO does not adversely affect cognitive function in the majority of cases.

Descriptive Analysis of the Components

The resulting treatment effect of a composite endpoint alone is often difficult to interpret as the individual components do not necessarily contribute the same amounts to this net effect. As discussed before, current guidelines therefore recommend to always analyze the components of composite endpoints separately. The current well-established practice is to provide descriptive analyses of the components and the composite in addition to the confirmatory analysis of the composite. However, there exist a number of different methods to evaluate the single components in a descriptive manner. In this chapter, the most common approaches for a descriptive analysis of the individual components will be presented and discussed. Moreover, we will deduce recommendations for a meaningful presentation and interpretation of the component-specific results.

Clinical Trial Examples with (Composite) Time-to-Event Endpoints

Similar to the previous chapter, we discuss in this chapter several original clinical trials for time-to-event composite endpoints along with their designs, results, and possible limitations. The focus is again to propose and apply alternative planning and analysis strategies which might help to improve the performance of the design or to ease interpretation of results.

Correlation Between Test Statistics

It is evident that the composite endpoint is, by definition, correlated to its components as every event related to a component is also an event in the composite. This correlation might be incorporated in different ways in the planning stage and/or the analysis of the trial and is hence of general interest. Therefore, in this chapter the correlations between a composite and a single component and the correlation between two individual components are deduced for binary and time-to-event endpoints.

Clinical Trial Examples with (Composite) Binary Endpoints

In this chapter, we discuss several original clinical trials for composite binary endpoints along with their designs, results, and possible limitations. The focus of this chapter is to propose and apply alternative planning and analysis strategies which might help to improve the performance of the design or to ease interpretation of results.

The Single-Stage Design

In this chapter, the test problem is introduced for the case of a standard single-stage design, meaning that no interim analysis is performed. The underlying parameters and distributional assumptions, the test problems, and the test statistics will be separately formulated for (composite) binary endpoints and for (composite) time-to-(first-)event endpoints. Moreover, approaches to calculate the required sample size are provided.