Ulrich Grouven

Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials.

Objectives To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential publication bias in trials of reboxetine. Design Systematic review and meta-analysis including unpublished data. Data sources Bibliographic databases (Medline, Embase, PsycINFO, BIOSIS, and Cochrane Library), clinical trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin). Eligibility criteria Double blind, randomised, controlled trials of acute treatment (six weeks or more) with reboxetine versus placebo or SSRIs in adults with major depression. Outcome measures Remission and response rates (benefit outcomes), as well as rates of patients with at least one adverse event and withdrawals owing to adverse events (harm outcomes). Data extraction and data synthesis The procedures for data extraction and assessment of risk of bias were always conducted by one person and checked by another. If feasible, data were pooled by meta-analyses (random effects model). Publication bias was measured by comparing results of published and unpublished trials. Results We analysed 13 acute treatment trials that were placebo controlled, SSRI controlled, or both, which included 4098 patients. Data on 74% (3033/4098) of these patients were unpublished. In the reboxetine versus placebo comparison, no significant differences in remission rates were shown (odds ratio 1.17, 95% confidence interval 0.91 to 1.51; P=0.216). Substantial heterogeneity (I2=67.3%) was shown in the meta-analysis of the eight trials that investigated response rates for reboxetine versus placebo. A sensitivity analysis that excluded a small inpatient trial showed no significant difference in response rates between patients receiving reboxetine and those receiving placebo (OR 1.24, 95% CI 0.98 to 1.56; P=0.071; I2=42.1%). Reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram) for remission rates (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 95% CI 0.67 to 0.95; P=0.01). Reboxetine was inferior to placebo for both harm outcomes (P<0.001 for both), and to fluoxetine for withdrawals owing to adverse events (OR 1.79, 95% CI 1.06 to 3.05; P=0.031). Published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm. Conclusions Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.

Using binary logistic regression models for ordinal data with non-proportional odds

The proportional odds model (POM) is the most popular logistic regression model for analyzing ordinal response variables. However, violation of the main model assumption can lead to invalid results. This is demonstrated by application of this method to data of a study investigating the effect of smoking on diabetic retinopathy. Since the proportional odds assumption is not fulfilled, separate binary logistic regression models are used for dichotomized response variables based upon cumulative probabilities. This approach is compared with polytomous logistic regression and the partial proportional odds model. The separate binary logistic regression approach is slightly less efficient than a joint model for the ordinal response. However, model building, investigating goodness-of-fit, and interpretation of the results is much easier for binary responses. The careful application of separate binary logistic regressions represents a simple and adequate tool to analyze ordinal data with non-proportional odds.

Automatic Classification Algorithms of the EEG Monitor Narcotrend for Routinely Recorded EEG Data from General Anaesthesia: a Validation Study

Impacts of hypnotic drugs on brain function are reflected in the EEG. The EEG monitor Narcotrend performs an automatic classification of the EEG using a scale which was proposed by Kugler for visual evaluation of the EEG. In this article the results of a validation study of the automatic classification algorithms implemented in the EEG monitor Narcotrend are presented. Visual and automatic classification of EEG data recorded in routine clinical practice were compared. The correlation between visual and automatic assessment was high (Spearman rank correlation r = 0.90, prediction probability Pk = 0.90) and a sufficient agreement between visual and automatic assessment was achieved for 92% of the analysed EEG epochs. The results of the study suggest that the automatic classification algorithms implemented in the EEG monitor Narcotrend yield a reliable assessment of the depth of hypnosis.

Permanent Interstitial Low-Dose-Rate Brachytherapy for Patients with Localised Prostate Cancer: A Systematic Review of Randomised and Nonrandomised Controlled Clinical Trials

CONTEXT Prostate cancer (PCa) is the most common cancer in men. Permanent interstitial low-dose-rate brachytherapy (LDR-BT) is a short-distance radiation therapy in which low-energy radioactive sources are implanted permanently into the prostate. OBJECTIVE To assess the effectiveness and safety of LDR-BT compared to treatment alternatives in men with localised PCa. EVIDENCE ACQUISITION Bibliographic databases (Medline, Embase, and the Cochrane Library) were searched from inception until June 2010 for randomised and nonrandomised controlled trials comparing LDR-BT with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or no primary therapy (NPT). Primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS), biochemical recurrence-free survival (bRFS), physician-reported severe adverse events (SAE), and patient-reported outcomes (PRO). EVIDENCE SYNTHESIS A total of 31 studies, including 1 randomised controlled trial (RCT), were identified. Risk of bias was high for all 31 studies. OS was reported in one nonrandomised controlled study; however, these data were not interpretable because of strong residual confounding. DFS was not reported. Comparison of bRFS between treatment groups is not validated; thus, results were not interpretable. Physician-reported urogenital late toxicity grade 2 to 3 was more common in the LDR-BT group when compared to the EBRT group. With respect to PRO, better scores for sexual and urinary function as well as urinary incontinence were reported for LDR-BT compared to RP. Better scores for bowel function were reported for LDR-BT compared to EBRT. CONCLUSIONS We found a low amount of evidence in studies that exclusively compared LDR-BT with other treatment modalities. LDR-BT may have some different physician-reported SAE and patient-reported outcomes. The current evidence is insufficient to allow a definitive conclusion about OS. Randomised trials focusing on long-term survival are needed to clarify the relevance of LDR-BT in patients with localised PCa.

Logistic regression models used in medical research are poorly presented.

EDITOR,—The application of multiple regression models in medical research has greatly increased during the past years.1 Nevertheless, assessing the accuracy of regression models in describing the data (goodness of fit) is almost unknown in medical research. Hence, medical journals may be publishing papers in which regression models are misused or results are misinterpreted. We investigated the use of logistic regression in papers published in the BMJ, JAMA, the Lancet, and the New England Journal of Medicine during 1991-4. A Medline …

Age-related effects in the EEG during propofol anaesthesia.

Background:  Age‐related differences in the spectral composition of the EEG in induction and emergence times, and in drug consumption during propofol anaesthesia were investigated.

The Narcotrend Index: Classification Algorithm, Correlation with Propofol Effect-Site Concentrations, and Comparison with Spectral Parameters / Der Narcotrend-Index: Klassifikationsalgorithmus, Korrelation mit Propofol-Effekt-Site-Konzentrationen und Vergleich mit Spektralparametern

Abstract A reliable assessment of the depth of hypnosis during sedation and general anaesthesia using the EEG is a subject of current interest. The Narcotrend Index implemented in the latest version 4.0 of the EEG monitor Narcotrend® provides an automatic classification of the EEG on a scale ranging from 100 (awake) to 0 (very deep hypnosis, EEG suppression). The classification algorithms implemented in the EEG monitor Narcotrend are described. In a study the correlation of the propofol effect-site concentration with the Narcotrend Index and with the traditional spectral parameters total power, relative power in the standard frequency bands δ, θ, α, and β, median frequency, 95 % spectral edge frequency, burst-compensated spectral edge frequency, and spectral entropy was investigated. The Narcotrend Index had the highest average correlation with the propofol effect-site concentration and the smallest variability of the individual correlation values. Moreover, the Narcotrend Index was the only parameter which showed a monophasic trend over the whole investigated time period. The Narcotrend monitor can make a significant contribution to the improvement of the quality of anaesthesia by adjusting the dosage of hypnotics to individual patient needs. Die zuverlässige Bewertung der Schlaftiefe während Sedierung und Narkose ist ein Thema von aktuellem Interesse. Der Narcotrend-Index, der in der neusten Version 4.0 des EEG-Monitors Narcotrend® implementiert ist, liefert eine automatische Klassifikation des EEG auf einer Skala von 100 (wach) bis 0 (tiefste Narkose). Die Klassifikationsalgorithmen des Narcotrend-EEG-Monitors werden beschrieben. In einer Studie wurde die Korrelation der Propofol-Effekt-Site-Konzentration mit dem Narcotrend-Index sowie mit den klassischen Spektralparametern Gesamtleistung, relative Leistung in den Standard-Frequenzbändern δ, θ, α und β, Median-Frequenz, 95 % spektrale Eckfrequenz, burst-korrigierte spektrale Eckfrequenz und spektrale Entropie untersucht. Der Narcotrend-Index zeigte die höchste mittlere Korrelation mit der Propofol-Effekt-Site-Konzentration und die geringste Streuung der individuellen Korrelationen. Zudem war der Narcotrend-Index der einzige Parameter, der einen monophasischen Trend über den gesamten untersuchten Zeitverlauf aufwies. Der Narcotrend kann einen wertvollen Beitrag zur Verbesserung der Narkosequalität durch eine individuell auf den einzelnen Patienten abgestimmte Hypnotika-Dosierung leisten.

Unrelated donor stem cell transplantation in acquired severe aplastic anemia: a systematic review

Acquired severe aplastic anemia is a rare disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells from unrelated donors is a treatment option frequently offered to patients after failed immunosuppressive therapy. This systematic review indicates that unrelated donor hematopoietic stem cell transplantation in patients with acquired severe aplastic anemia after failure of immunosuppressive therapy is a valid treatment option. Acquired severe aplastic anemia is a rare disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells from unrelated donors is a treatment option frequently offered to patients after failed immunosuppressive therapy. The aim was to investigate the outcome of these patients treated with unrelated donor transplants. Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to June 2009. Only full-text publications and studies including at least 10 patients were considered. The primary outcome was 5-year overall survival from the day of transplantation and the secondary outcomes were graft failure and graft-versus-host disease. A meta-analysis of survival estimates was conducted and heterogeneity was investigated. A total of 18 studies, one controlled trial and 17 case series were identified. The overall survival at five years and the corresponding confidence interval was stated in 8 studies and ranged from 28% to 94%. A meta-analysis revealed considerable heterogeneity between the studies that could not be explained and was also present in subgroups of the studies. The proportion of acute graft failure was 45% in one study using only umbilical cord blood, and it was reported to be 0–26% in 15 studies using mainly bone marrow as stem cell source after different follow-up periods. Acute GVHD grade II–IV was reported for 8–86% and extensive chronic GVHD for 0–38% of the evaluated patients in 16 studies. Recipient age, human leukocyte antigen match, performance status, year of transplantation, and conditioning with serotherapy were identified as significant factors for improved survival. Unrelated donor hematopoietic stem cell transplantation in patients with acquired severe aplastic anemia after failure to immunosuppressive therapy is a treatment option. A stable physical condition of the patients before receiving the transplant (for example, performance and age) may be associated with a better survival. Detailed HLA-matching facilitated by DNA-based typing, among other factors, may have contributed to recent improvements on survival after unrelated donor HSCT as a second-line treatment.

Correlation of Narcotrend Index, entropy measures, and spectral parameters with calculated propofol effect-site concentrations during induction of propofol–remifentanil anaesthesia

Objective. The aim of this study was to compare the EEG parameter Narcotrend Index with the spectral and entropy-based EEG parameters median frequency, 95% spectral edge frequency, burst-compensated 95% spectral edge frequency, spectral entropy, amplitude entropy, and approximate entropy with regard to their ability to describe cerebral anaesthetic drug effects during induction of propofol–remifentanil anaesthesia. Methods. Three induction schemes were studied with 10 patients each receiving 2 mg propofol/kg/60s (group 1), 4 mg/kg/120s (group 2), and 4 mg/kg/240s (group 3). The EEG was recorded with the EEG monitor Narcotrend®. To analyse the relation between drug effect and EEG parameters, Spearman rank correlation of the different EEG parameters with the calculated propofol effect-site concentration was computed. Results. In all groups Narcotrend Index showed the highest correlation with the propofol effect-site concentration and the lowest variability of individual correlation values. Furthermore, only the Narcotrend Index showed a monophasic behaviour over the entire time period analysed. In the group of entropy parameters approximate entropy yielded the best results. Among the spectral parameters the burst-compensated 95% spectral edge frequency had the highest correlation with the propofol effect-site concentration. It was markedly higher than for the standard spectral edge frequency. The correlations of median frequency and amplitude entropy with propofol effect-site concentration were the lowest. Conclusions. Changes in the propofol effect-site concentration during induction of anaesthesia were best described by the multivariate Narcotrend Index compared to conventional spectral EEG parameters and different entropy measures.

First-Line Matched Related Donor Hematopoietic Stem Cell Transplantation Compared to Immunosuppressive Therapy in Acquired Severe Aplastic Anemia

Introduction Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials. Methods A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival. Results 26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies. Conclusions Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.