Gernot Wassmer

Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30 000 patients

AIMS To determine the strength of evidence for preoperative statin use for prevention of adverse postoperative outcomes in patients undergoing cardiac surgery. METHODS AND RESULTS After literature search in major databases, 19 studies were identified [three RCT (randomized prospective clinical trials), 16 observational] that reported outcomes of 31 725 cardiac surgery patients with (n = 17 201; 54%) or without (n = 14 524; 46%) preoperative statin therapy. Outcomes that were analysed included early all-cause mortality (30-day mortality), myocardial infarction (MI), atrial fibrillation (AF), stroke and renal failure. Odds ratio (OR) with 95% confidence intervals (95%CI) were reported using fixed or random effect models and publication bias was assessed. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95%CI: 0.49-0.67). A significant reduction (P < 0.01) in statin pretreated patients was also observed for AF (24.9 vs. 29.3%; OR 0.67, 95%CI: 0.51-0.88), stroke (2.1 vs. 2.9%, OR 0.74, 95%CI: 0.60-0.91), but not for MI (OR 1.11; 95%CI: 0.93-1.33) or renal failure (OR 0.78, 95%CI: 0.46-1.31). Funnel plot and Eggers regression analysis (P = 0.60) excluded relevant publication bias. CONCLUSION Our meta-analysis provides evidence that preoperative statin therapy exerts substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients, but underscores the need for RCT trials.

Statins for prevention of atrial fibrillation after cardiac surgery: a systematic literature review

OBJECTIVE To determine the strength of evidence of preoperative statin therapy for prevention of atrial fibrillation after cardiac surgery. METHODS A meta-analysis was performed of randomized controlled trials and observational trials reporting the impact of preoperative statin therapy on the incidence of any type and new-onset atrial fibrillation after cardiac surgery. Unadjusted and adjusted treatment effects (odds ratio, 95% confidence intervals) were pooled using a random-effects model, and publication bias was assessed. RESULTS Thirteen studies were identified (3 randomized controlled trials, 10 observational trials) that reported the incidence of postoperative atrial fibrillation in 17,643 patients having cardiac surgery with (n = 10,304; 58%) or without (n = 7339; 42%) preoperative statin use. New-onset atrial fibrillation was reported in a total of 7855 patients. Postoperative incidence rates for any or new-onset atrial fibrillation were 24.6% and 29.9%, respectively. Preoperative statin use resulted in a 22% and 34% unadjusted odds reduction for any atrial fibrillation (odds ratio, 0.78; 95% confidence interval, 0.67-0.90) or new-onset atrial fibrillation (odds ratio, 0.66; 95% confidence interval, 0.51-0.84) after surgery (P < .001). Relevant publication bias and an unequal distribution of confounding variables favoring patients treated with statins were identified. Nevertheless, the beneficial actions of statins on atrial fibrillation persisted after pooled analysis of risk-adjusted treatment effects from randomized controlled trials and observational trials (any atrial fibrillation-odds ratio, 0.64; 95% confidence interval, 0.48-0.87; new-onset atrial fibrillation-odds ratio, 0.66; 95% confidence intervals, 0.48-0.89; P < .01). CONCLUSION Our meta-analysis provides evidence that preoperative statin therapy is associated with a reduction in the incidence of atrial fibrillation after cardiac surgery.

Hypertension guidelines and their limitations--the impact of physicians' compliance as evaluated by guideline awareness.

Objective The initial step of an optimal therapeutic strategy for patients with arterial hypertension is the recognition and acceptance of new recommendations by the physicians themselves. This guideline awareness of the physicians has never been evaluated in detail. Design The awareness of content of current recommendations in hypertension diagnosis, treatment and treatment control was therefore assessed in primary care physicians using a questionnaire. The guidelines of the German Hypertension Society were used as the reference standard. Participants A total of 24 899 German physicians, including all internists, all cardiologists and 22% of general practitioners were contacted in a nationwide survey. Main outcome measures The number of answers in agreement with the guideline was used as a measure of guideline awareness. Adequate awareness of content of guideline recommendations was defined as the correct answer to five out of eight questions; the correct answers had to include the appropriate definition of hypertension. Results The analysis was based on 11 547 returned questionnaires (47.1%). An adequate guideline awareness was found in 23.7% of the total study population, especially in 37.1% of cardiologists, in 25.6% of internists and in 18.8% of general practitioners. While the guideline awareness was significantly influenced by the duration of private practice, regional and municipal factors had only minor influence on the results. Conclusion The impact of hypertension guidelines on actual medical knowledge is modest. Thus, the information strategies about current treatment guidelines must be improved and tailored to the needs of physicians in clinical practice to ultimately improve patient care.

A COMPARISON OF TWO METHODS FOR ADAPTIVE INTERIM ANALYSES IN CLINICAL TRIALS

Recently, two methods for planning and conducting two-stage procedures were proposed (Bauer and Köhne, 1994, Biometrics 50, 1029-1041; Proschan and Hunsberger, 1995, Biometrics 51, 1315-1324). Both procedures allow the termination of the trial with the early acceptance of H0 in the absence of a treatment effect after performing the first stage of the study. Furthermore, the observed treatment effect at stage I can be used for planning and redesigning the second stage of the study in a way that protects the Type I error rate. The exact Type I error rate of the Proschan and Hunsberger approach is derived. It is shown that the two methods lead to similar decision rules with negligibly small differences in power and expected sample size. In terms of providing design tools and practical applicability, however, they differ. The practical performance of the procedures is discussed and recommendations for their use are given.

Twenty‐five years of confirmatory adaptive designs: opportunities and pitfalls

‘Multistage testing with adaptive designs’ was the title of an article by Peter Bauer that appeared 1989 in the German journal Biometrie und Informatik in Medizin und Biologie. The journal does not exist anymore but the methodology found widespread interest in the scientific community over the past 25 years. The use of such multistage adaptive designs raised many controversial discussions from the beginning on, especially after the publication by Bauer and Köhne 1994 in Biometrics: Broad enthusiasm about potential applications of such designs faced critical positions regarding their statistical efficiency. Despite, or possibly because of, this controversy, the methodology and its areas of applications grew steadily over the years, with significant contributions from statisticians working in academia, industry and agencies around the world. In the meantime, such type of adaptive designs have become the subject of two major regulatory guidance documents in the US and Europe and the field is still evolving. Developments are particularly noteworthy in the most important applications of adaptive designs, including sample size reassessment, treatment selection procedures, and population enrichment designs. In this article, we summarize the developments over the past 25 years from different perspectives. We provide a historical overview of the early days, review the key methodological concepts and summarize regulatory and industry perspectives on such designs. Then, we illustrate the application of adaptive designs with three case studies, including unblinded sample size reassessment, adaptive treatment selection, and adaptive endpoint selection. We also discuss the availability of software for evaluating and performing such designs. We conclude with a critical review of how expectations from the beginning were fulfilled, and – if not – discuss potential reasons why this did not happen.

Continuous Infusion of Clonidine in Ventilated Newborns and Infants: A Randomized Controlled Trial

Objectives: To assess the influence of an infusion of clonidine 1 &mgr;g/kg/hr on fentanyl and midazolam requirement in ventilated newborns and infants. Design: Prospective, double-blind, randomized controlled multicenter trial. Controlled trials.com/ISRCTN77772144. Setting: Twenty-eight level 3 German PICUs/neonatal ICUs. Patients: Ventilated newborns and infants: stratum I (1–28 d), stratum II, (29–120 d), and stratum III (121 d to 2 yr). Interventions: Patients received clonidine 1 &mgr;g/kg/hr or placebo on day 4 after intubation. Fentanyl and midazolam were adjusted to achieve a defined level of analgesia and sedation according to Hartwig score. Measurements and Main Results: Two hundred nineteen infants were randomized; 212 received study medication, 69.7% were ventilated in the postoperative care and 30.3% for other reasons. Primary endpoint: consumption of fentanyl and midazolam in the 72 hours following the onset of study medication (main observation period) in the overall study population. The confirmatory analysis of the overall population showed no difference in the consumption of fentanyl and midazolam. Explorative age-stratified analysis demonstrated that in stratum I (n = 112) the clonidine group had a significantly lower consumption of fentanyl (clonidine: 2.1 ± 1.8 &mgr;g/kg/hr, placebo: 3.2 ± 3.1 &mgr;g/kg/hr; p = 0.032) and midazolam (clonidine: 113.0 ± 100.1 &mgr;g/kg/hr, placebo: 180.2 ± 204.0 &mgr;g/kg/hr; p = 0.030). Strata II (n = 43) and III (n = 46) showed no statistical difference. Sedation and withdrawal-scores were significantly lower in the clonidine group of stratum I (p < 0.001). Frequency of severe adverse events did not differ between groups. Conclusions: Clonidine 1 &mgr;g/kg/hr in ventilated newborns reduced fentanyl and midazolam demand with deeper levels of analgesia and sedation without substantial side effects. This was not demonstrated in older infants, possibly due to lower clonidine serum levels.

Association of the vitamin D receptor genotype with bone metastases in breast cancer patients.

This study was designed in order to evaluate specific vitamin D receptor (VDR) genotypes as indicators of the likelihood of developing osseous metastases in breast cancer patients. Therefore, we determined polymorphisms of the VDR gene in a study group comprising 183 breast cancer patients. Specific fragments spanning over intron 8 and exon 9 of the VDR gene were amplified by polymerase chain reaction. The fragments were then incubated with each of the specific endonucleases ApaI, BsmI or TaqI, respectively. The VDR gene polymorphisms were detected by the presence or absence of the particular restriction site using agarose gel electrophoresis. Statistical analyses revealed a significant correlation between both the VDR gene polymorphisms indicated as AA (absence of the ApaI restriction site in both alleles) or TT (absence of the TaqI restriction site in both alleles), respectively, and the occurrence of bone metastases. Patients with the AA genotype have a 1.7-fold increased risk of developing bone metastases, whereas patients with the TT genotype have a 0.5-fold risk. Neither other genotypes nor allelic combinations displayed any further correlation with the clinical stage. The data suggest that the AA genotype of the VDR gene might be useful to identify breast cancer patients with a high probability of forming occult bone metastases who are considered to benefit from an adjuvant bone-protective therapy.

Flexible Interim Analyses in Clinical Trials Using Multistage Adaptive Test Designs

Data-dependent interim analyses are a useful tool in confirmatory Phase III or IV clinical research. In particular, redesigning the sample size in an interim analysis based on the results observed to date considerably improves the power of the trial since the best available information at the time is used for the sample size adjustment. In recent years, several methods were proposed that enable a flexible design through the use of adaptive interim analyses while maintaining the type I error rate. In this article, these methods are briefly reviewed. We recommend a strategy that copes well with the demands of practice. Examples illustrate the use of multistage adaptive designs that make it possible to calculate confidence intervals and bias adjusted point estimates.

Procedures for testing multiple endpoints in clinical trials: An overview

Abstract This article gives an overview of statistical methods applicable in standard clinical trials where a multivariate outcome is measured in two groups of subjects. We refer to some recently proposed methods that take into account the directionality of the alternative. In particular, we describe a linear combination statistic which serves as an alternative to the usual Hotellings T2 statistic. Furthermore, we focus on the simultaneous consideration of the endpoints through resampling since these methods turn out to provide a reasonable and powerful tool for analyses. The application of the procedures in a closed testing procedure is described. Some nonparametric tests, the missing data problem, and recent developments on interim analyses solutions are outlined.

Basic concepts of group sequential and adaptive group sequential test procedures

Based on the concept of repeated significance tests, an empirical study may be planned in subsequent stages. Group sequential test procedures offer the possibility of performing the study with a fixed number of observations per stage. At least, the number of observations must be chosen independently of the observed data. In adaptive group sequential test procedures, the number of observations can be changed during the course of the study using all results observed so far. In this article, the basic concepts of these two designs are reviewed. Recent developments in adaptive designs are outlined and potential fields of application are given.